Preparation method of ivermectin
By hydrogenating avermectin with triphenylphosphine rhodium chloride and tetrabutyl ammonium bromide under a hydrogen atmosphere, the reaction conditions are optimized, and the long reaction time and triphenylphosphine chloride in the prior art are solved. The problem of large amount of rhodium has achieved efficient preparation of ivermectin, reducing production costs and improving conversion rates.
Patent Information
- Application Number
- CN202411319914.4
- Authority / Receiving Office
- CN · China
- Patent Type
- Applications(China)
- Current Assignee / Owner
- Filing Date
- 2024-09-20
- Publication Date
- 2024-12-27
AI Technical Summary
In the existing ivermectin preparation method, the reaction time is long and the amount of triphenylphosphonium rhodium chloride is used, resulting in high production costs.
Mix avermectin, triphenylphosphonium rhodium chloride and tetrabutyl ammonium bromide as catalyst aids under a hydrogen atmosphere, and prepare ivermectin by hydrogenation reaction, optimize the reaction conditions including temperature, pressure and catalyst ratio , reduce the amount of triphenylphosphonium rhodium chloride.
The reaction time is shortened, the amount of triphenylphosphonium rhodium chloride is reduced, the raw material conversion rate is improved, the production cost is low, and the conversion rate of avermectin reaches more than 99%.
Smart Images
Figure BDA0005053596270000041
Abstract
Description
Technical Field
[0001] The invention belongs to the technical field of biological drug preparation, and particularly relates to a method for preparing ivermectin. Background Art
[0002] Ivermectin is a new type of macrolide antibiotic anthelmintic with the advantages of high efficiency, broad spectrum and low toxicity. It is widely used to kill animal and plant parasites and is one of the biological pesticides with great development potential.
[0003] At present, the pharmaceutical industry mainly uses avermectin as raw material, and produces ivermectin through hydrogenation reaction under the catalytic action of triphenylphosphine rhodium chloride. The disadvantages of this method are long reaction time, large amount of triphenylphosphine rhodium chloride, and high price of triphenylphosphine rhodium chloride, which increases the production cost of ivermectin. Summary of the invention
[0004] The object of the present invention is to provide a preparation method of ivermectin. The preparation method provided by the present invention has short reaction time, small amount of triphenylphosphine rhodium chloride used and low production cost.
[0005] In order to achieve the above-mentioned object of the invention, the present invention provides the following technical solutions:
[0006] The present invention provides a method for preparing ivermectin, comprising the following steps:
[0007] Avermectin, triphenylphosphine rhodium chloride, a catalyst aid and a solvent are mixed, and a hydrogenation reaction is carried out under a hydrogen atmosphere to obtain the ivermectin; the catalyst aid is tetrabutylammonium bromide.
[0008] Preferably, the solvent is toluene.
[0009] Preferably, the solid-liquid ratio of avermectin to solvent is 1 g: 2-3 mL.
[0010] Preferably, the mass ratio of avermectin to triphenylphosphine rhodium chloride is 200:0.3-0.5.
[0011] Preferably, the mass ratio of triphenylphosphine rhodium chloride to the catalyst aid is 3-5:1-2.
[0012] Preferably, the mass ratio of triphenylphosphine rhodium chloride to the catalyst promoter is 3:2, 4:1.5 or 5:1.
[0013] Preferably, the temperature of the hydrogenation reaction is 80-85°C.
[0014] Preferably, the hydrogenation reaction time is 1 h to 1.5 h.
[0015] Preferably, the pressure of the hydrogenation reaction is 1.3-1.5 MPa.
[0016] Preferably, the avermectin, triphenylphosphine rhodium chloride, catalyst promoter and solvent are mixed under nitrogen protection conditions.
[0017] The present invention provides a method for preparing ivermectin, comprising the following steps: mixing avermectin, triphenylphosphine rhodium chloride, a catalyst aid and a solvent, and performing a hydrogenation reaction under a hydrogen atmosphere to obtain the ivermectin; the catalyst aid is tetrabutylammonium bromide. The catalyst aid tetrabutylammonium bromide is added to reduce the amount of triphenylphosphine rhodium chloride. The preparation method provided by the present invention has the advantages of less amount of catalyst triphenylphosphine rhodium chloride, short reaction time, low production cost and high raw material conversion rate. The embodiment shows that by using the method provided by the present invention to prepare ivermectin, the residual rate of avermectin can be less than 1% in a relatively short time, that is, the avermectin conversion rate is above 99%.
[0018] Furthermore, compared with the prior art, the present invention increases the reaction temperature and pressure during the preparation of ivermectin, and effectively shortens the reaction time. DETAILED DESCRIPTION
[0019] The present invention provides a method for preparing ivermectin, comprising the following steps:
[0020] Avermectin, triphenylphosphine rhodium chloride, a catalyst aid and a solvent are mixed, and a hydrogenation reaction is carried out under a hydrogen atmosphere to obtain the ivermectin; the catalyst aid is tetrabutylammonium bromide.
[0021] In the present invention, unless otherwise specified, the raw materials used are commercially available products well known to those skilled in the art or are prepared by methods well known to those skilled in the art.
[0022] In the present invention, triphenylphosphine rhodium chloride is used as a catalyst; the mass ratio of avermectin to triphenylphosphine rhodium chloride is preferably 200:0.3-0.5, more preferably 200:0.3, 200:0.4 or 200:0.5.
[0023] In the present invention, the catalyst aid is tetrabutylammonium bromide; the mass ratio of the triphenylphosphine rhodium chloride to the catalyst aid is preferably 3-5:1-2, more preferably 3:2, 4:1.5 or 5:1.
[0024] In the present invention, the solvent is preferably toluene; the solid-liquid ratio of avermectin to the solvent is preferably 1 g: 2-3 mL, more preferably 1 g: 2.5 mL.
[0025] The avermectin, triphenylphosphine rhodium chloride, catalyst promoter and solvent of the present invention are preferably mixed under nitrogen protection. The present invention preferably dissolves avermectin in a solvent to obtain an avermectin solution; nitrogen is charged for displacement protection, and triphenylphosphine rhodium chloride and catalyst promoter are added to the avermectin solution. After the avermectin, triphenylphosphine rhodium chloride, catalyst promoter and solvent are mixed, the present invention preferably raises the temperature of the obtained mixed liquid to the required temperature for hydrogenation reaction under nitrogen protection, passes hydrogen to make the pressure reach the required conditions for hydrogenation reaction, and carries out hydrogenation reaction. In the present invention, the temperature of the hydrogenation reaction is preferably 80-85°C, specifically 80°C, 81°C, 82°C, 83°C, 84°C or 85°C; the time is preferably 1-1.5h, more preferably 1h; the pressure is preferably 1.3-1.5MPa, specifically 1.3MPa, 1.4MPa or 1.5MPa.
[0026] The technical solutions in the present invention will be described clearly and completely below in conjunction with the embodiments of the present invention. Obviously, the described embodiments are only a part of the embodiments of the present invention, not all of them. Based on the embodiments of the present invention, all other embodiments obtained by ordinary technicians in this field without creative work are within the scope of protection of the present invention.
[0027] Example 1
[0028] 500 mL of toluene was added into the reactor, and 200 g of avermectin was added, and the temperature was raised to 80° C. to dissolve the avermectin.
[0029] Fill the reactor with nitrogen to replace the air in the reactor, then add 0.5g of triphenylphosphine rhodium chloride and 0.1g of tetrabutylammonium bromide, and tighten the bolts of the reactor. Raise the temperature of the reactor to 80°C, fill with hydrogen until the pressure of the reactor is 1.3-1.5MPa, and carry out hydrogenation reaction to prepare ivermectin under the above conditions, and ensure that the reaction pressure is not less than 1.3MPa during the reaction.
[0030] After the hydrogenation reaction was carried out for 1 hour, the obtained reaction liquid was sampled and the avermectin residue in the reaction liquid was detected by high performance liquid chromatography (HPLC). The detection results showed that the avermectin residue in the reaction liquid was 0.50%, that is, the conversion rate of avermectin was 99.5%, and the detection was qualified.
[0031] Example 2
[0032] The amount of triphenylphosphine rhodium chloride was adjusted to 0.3 g, the amount of tetrabutylammonium bromide was adjusted to 0.2 g, the reaction temperature was adjusted to 85° C., and the other conditions were the same as in Example 1.
[0033] After the hydrogenation reaction was carried out for 1 hour, the obtained reaction liquid was sampled and the avermectin residue in the reaction liquid was detected by HPLC. The detection result showed that the avermectin residue in the reaction liquid was 0.30%, that is, the conversion rate of avermectin was 99.70%, and the detection was qualified.
[0034] Comparative Example 1 (conventional method)
[0035] 500 mL of toluene was added into the reactor, and 200 g of avermectin was added, and the temperature was raised to 80° C. to dissolve the avermectin.
[0036] Fill the reactor with nitrogen to replace the air in the reactor, then add 1g of triphenylphosphine rhodium chloride, and tighten the bolts of the reactor. Raise the temperature of the reactor to 75°C, fill with hydrogen until the pressure of the reactor is 0.8-1.1MPa, and carry out hydrogenation reaction to prepare ivermectin under the above conditions, and ensure that the reaction pressure is not less than 0.8MPa during the reaction.
[0037] After the hydrogenation reaction was carried out for 3.5 hours, the obtained reaction liquid was sampled and the avermectin residue in the reaction liquid was detected by HPLC. The detection results showed that the avermectin residue in the reaction liquid was 0.70%, that is, the conversion rate of avermectin was 99.30%, and the detection was qualified.
[0038] Comparative Example 2
[0039] The amount of triphenylphosphine rhodium chloride was adjusted to 0.5 g, tetrabutylammonium bromide was not added, the reaction temperature was adjusted to 80° C., and the other conditions were the same as in Example 1.
[0040] After the hydrogenation reaction was carried out for 1 hour, the obtained reaction liquid was sampled and the avermectin residue in the reaction liquid was detected by HPLC. The detection results showed that the avermectin residue in the reaction liquid was 1.20%, that is, the conversion rate of avermectin was 98.80%.
[0041] Comparative Example 3
[0042] The amount of triphenylphosphine rhodium chloride was adjusted to 0.5 g, the amount of tetrabutylammonium bromide was adjusted to 0.1 g, the reaction temperature was adjusted to 75° C., and the other conditions were the same as in Example 1.
[0043] After the hydrogenation reaction was carried out for 1 hour, the obtained reaction liquid was sampled and the avermectin residue in the reaction liquid was detected by HPLC. The detection result showed that the avermectin residue in the reaction liquid was 0.60%, that is, the conversion rate of avermectin was 99.4%.
[0044] Comparative Example 4
[0045] The amount of triphenylphosphine rhodium chloride was adjusted to 0.5 g, the amount of tetrabutylammonium bromide was adjusted to 0.1 g, the reaction pressure was adjusted to 0.8-1.1 MPa, and the other conditions were the same as in Example 1.
[0046] After the hydrogenation reaction was carried out for 1 hour, the obtained reaction liquid was sampled and the avermectin residue in the reaction liquid was detected by HPLC. The detection result showed that the avermectin residue in the reaction liquid was 0.8%, that is, the conversion rate of avermectin was 99.2%.
[0047] The preparation conditions and experimental results of Examples 1 to 2 and Comparative Examples 1 to 4 are shown in Table 1.
[0048] Table 1 Preparation conditions and experimental results of Examples 1 to 2 and Comparative Examples 1 to 4
[0049]
[0050] As can be seen from Table 1, compared with Comparative Example 1 using a conventional method, the preparation method provided by the present invention has a short synthesis cycle, a small amount of catalyst triphenylphosphine rhodium chloride is used, and the conversion rate of avermectin is improved; compared with Comparative Examples 2 to 4, the preparation method provided by the present invention can effectively improve the conversion rate of avermectin.
[0051] Although the above embodiment describes the present invention in detail, it is only a part of the embodiments of the present invention, not all of the embodiments. People can also obtain other embodiments based on this embodiment without creativity, and these embodiments all fall within the protection scope of the present invention.
Claims
1. A method for preparing ivermectin, characterized in that: The following steps are involved: Avermectin, triphenylphosphine rhodium chloride, a catalyst aid and a solvent are mixed, and a hydrogenation reaction is carried out under a hydrogen atmosphere to obtain the ivermectin; the catalyst aid is tetrabutylammonium bromide.
2. The preparation method according to claim 1, characterized in that: The solvent is toluene.
3. The preparation method according to claim 1 or 2, characterized in that: The solid-liquid ratio of the avermectin to the solvent is 1 g: 2-3 mL.
4. The preparation method according to claim 1, characterized in that: The mass ratio of avermectin to triphenylphosphine rhodium chloride is 200:0.3-0.
5.
5. The preparation method according to claim 1, characterized in that: The mass ratio of the triphenylphosphine rhodium chloride to the catalyst aid is 3-5:1-2.
6. The preparation method according to claim 5, characterized in that: The mass ratio of the triphenylphosphine rhodium chloride to the catalyst aid is 3:2, 4:1.5 or 5:
1.
7. The preparation method according to claim 1, characterized in that: The temperature of the hydrogenation reaction is 80-85°C.
8. The preparation method according to claim 1 or 7, characterized in that: The hydrogenation reaction time is 1 to 1.5 hours.
9. The preparation method according to claim 1 or 7, characterized in that: The pressure of the hydrogenation reaction is 1.3-1.5 MPa.
10. The preparation method according to claim 1, characterized in that: The avermectin, triphenylphosphine rhodium chloride, catalyst promoter and solvent are mixed under nitrogen protection conditions.