JP2000509729A - Method for producing ivermectin - Google Patents

Abstract

  (57) [Summary] Disclosed is a method for producing ivermectin by reducing avermectin, which can provide a final product having high purity in a very quantitative yield.

Description

DETAILED DESCRIPTION OF THE INVENTION                     Method for producing ivermectin   The present invention relates to a method for producing ivermectin by reduction from avermectin. Things.   Ivermectin (22,23-dihydroavermectin) has a parasiticidal activity (anti-parasitic activity). Insecticides, ectoparasiticides, insecticides and acaricides) Used in either human treatment or veterinary or agricultural fields.   The selective reduction of avermectin to ivermectin is known and requires Made with a complex between uranium (I) and three molecules of triphenylphosphine It is carried out in a homogeneous phase with a Kinson catalyst.   The reduction disclosed in U.S. Pat. No. 4,199,569 uses the five Is the only cis-di-substituted double bond with little steric hindrance. The 2,23-double bond is site-specifically hydrogenated.   Treatment of the reaction product to recover ivermectin by known methods is extremely challenging. Will be defeated. In fact, first the solvent (now Toluene) until an oily residue is obtained, which is recovered with a solvent to give a solution. From which ivermectin is isolated by crystallization with the addition of an insolubilizing agent (generally water) It is necessary to. The first precipitate of ivermectin is catalyzed by Wilkinson's catalyst. The reaction was carried out in a containing medium, so that the final product contained significant amounts of rhodium (100-2 00 ppm) as an impurity.   Improve rhodium recovery and reduce its content in ivermectin In a variant (disclosed in US Pat. No. 4,413,118), the reaction product is an organic solvent Treated with a compound having a carbon-sulfur double bond (especially thiourea) under reflux in To isolate the rhodium complex, which is then metal recovered and fresh Wilkinson Towards the creation of a catalyst. Reactivity showing significant ecological and environmental disadvantages Large amounts of thiourea (2-12 mol / 1 mol rhodium) Still used in this process.   This time, a dimer of rhodium chloride 1,5-cyclooctadiene and at least one The following formula is created in situ by the reaction between the phosphine and [P (ArXn₁) (ArXn_Two) (ArXn_Three)] ・ NNa Wherein Ar is an aryl group, and X is a sulfone group SO_ThreeAnd n₁, N_TwoAnd And n_ThreeAre independently equal to 0 or 1;₁+ N_Two+ N_ThreeIs 0 Greater than or equal to n, which is an integer equal to 0] Reducing avermectin in the presence of a catalyst having A dimer of 1,5-cyclooctadiene and the at least one phosphine A molar ratio between 1: 3 and 1:12, preferably 1: 6. A method for producing lumectin has been found, which is the subject of the present invention.   Preferably Ar is a phenyl group C₆H_Five-.   The process of the present invention achieves reduction in the presence of a solvent in both the homogeneous and heterogeneous phases. Can be done.   In a homogeneous phase, the process of the present invention is characterized in that n is greater than 1 or If equal to 1, a linear or branched C₁~ C_FourAlkyl alcohol (for example, Select from methanol, ethanol, isopropanol, especially isopropanol) Alcoholic or aliphatic chlorinated solvents used (eg methylene chloride) Or use of an aliphatic esterification solvent (eg, ethyl acetate), and the following steps: (A) recovering the catalyst from the solution containing the reaction product by cooling and filtration; (B) recovering ivermectin from the resulting solution by known techniques; Depending (C) Recycle the recovered catalyst after its sufficient regeneration for subsequent reduction Process.   In practice, most of the catalyst recovered by filtration after the above steps is cooled. The catalyst, which has precipitated from the reaction product and has been suitably regenerated, can be re-used for subsequent reduction, if necessary. used. Ivermectin is finally isolated from alcoholic solution by known techniques Is done.   For example, ivermectin recovery is described in US Pat. No. 4,199,569 and US Pat. No. 118, the obtained ivermectin solution is dissolved in an organic solvent (generally, toluene). In thiourea under reflux and the amount of thiourea (2 to 12 moles / mole of rhodium) compared to the amount disclosed in the aforementioned U.S. Patent Notably low.   When using a phosphine of the above formula where n = 0, the method of the present invention provides an aromatic, Alcoholic, aliphatic chlorinated or aliphatic Including the use of sterilized organic solvents. Toluene, isopropanol, methylene chloride Or ethyl acetate is preferred.   The process of the invention comprises the steps of reacting a sulfonated phosphine and an aromatic, aliphatic, Aliphatic chlorinated or aliphatic esterified organic solvents (preferably toluene) and Including the use of a solvent (preferably water) that is immiscible with the organic solvent. First organic phase Contains avermectin and a dimer of rhodium chloride 1,5-cyclooctadiene. The immiscible phase contains the sulfonated phosphine and, if necessary, a phase transfer agent, Transfer agents are compounds currently used in the art, particularly quaternary ammonium salts and salts. Alkylsulfonate, preferably the phase transfer agent is tetrabromide Butyl ammonium.   The method of the present invention, in a heterogeneous phase, further comprises the following steps: (Α) separating each layer; (Β) recovering the ivermectin from the organic phase according to known techniques; Depending (Γ) Recycle catalyst to organic phase and immiscible phase Each process.   For example, the recovery of ivermectin in a heterogeneous phase is described in US Pat. In accordance with the disclosure of U.S. Pat. Concentrate the organic phase containing mectin and mix it with formamide and water And then cooled, filtered and washed further to isolate the final product.   The reduction in both homogeneous and heterogeneous phases is at 20-70 ° C, preferably 45-70 ° C. The reaction is performed at a temperature of 65 ° C. and a pressure of 4 to 8 atm, preferably 5 to 7 atm.   The method of the present invention performs selective reduction of avermectin to ivermectin High purity and extremely quantitative yield, significantly reducing by-products To allow the use of rhodium amounts 10 times lower than those used in known methods. Make it work.   The most preferred sulfonated phosphine according to the present invention is diphenylphosphinobenze Sodium methanesulfonate.   The present invention replaces Wilkinson's catalyst when using sulfonated phosphines The catalyst complex according to the process of It belongs to a class of catalysts well-known in the publications used in oxo synthesis, such as catalysis.   In addition, these catalysts have the specificity of being water-soluble, Can be used in a double-phase reaction. Its creation and use is described in Chat t et al. Chem Soc. (1958), 276, 88; F. Bowsky et al., Nouveau Journal de Chemie ( 1977), Vol. 2, No. 2, pp. 137-144; Joo and M.S. T. Bech, Reac. Kin. and Cat. Letters (1975), Vol. 2, No. 3, pp. 257-263; Kuntz, Chemtech. ( September 1987).   The advantages arising from the use of these sulfonation catalyst systems are that the catalyst can be easily separated and re-used. On the cycle. In fact, the reaction products can be removed without conversion or destruction of the catalyst. If expensive catalysts are used, such as those containing rhodium, Due care has been taken.   Another advantage of performing the method of the invention in a heterogeneous phase is that Compared to the method of the invention and the method known using the Wilkinson catalyst, Is further reduced.   Further, the subject of the present invention is ivermectin in either a homogeneous or heterogeneous phase. The ivermectin solution, which was initially formed, was concentrated. Then, the obtained concentrate is mixed with an aqueous / alcoholic solvent mixture (here, in the mixture, Water is 10 to 30% and the alcohol is linear or branched C₁~ C_FourA With a styrene-divinylbenzene matrix Nonionic resin for adsorption (resin / ivermectin ratio per 1g ivermectin) (Ranging from 5 to 80 mL).   The recovery of ivermectin according to the invention is therefore preferably carried out in a homogeneous phase or Substrates arising from any of the heterogeneous phases can be combined with aqueous-alcoholic solvents (most preferred). Alcohols are methanol, ethanol and isopropanol) Nonionic resin for adsorption having a styrene-divinylbenzene matrix (H P series and SP series, manufactured by Mitsubishi Kasei) It can be done by doing. The resulting ivermectin elutes in the mobile phase Rhodium, on the other hand, remains bound to the stationary phase.   The recovery of ivermectin according to a preferred aspect of the invention amounts to 85-90% Very high yields with very low rhodium content in very high yields You can get things. This type of recovery further reduces the extraordinary impurities of this method Also enable.   Furthermore, the recovery according to the above aspect of the invention has the advantage of avoiding the use of thiourea. Is also shown.   Hereinafter, the present invention will be further described by way of examples without limitation.Example 1 Preparation of sulfonated phosphine   J. Chem. Soc. (1958), vol. 276, p. 88 A sulfonated phosphine was prepared according to the method. 10 g of triphenylphosphine Carefully added to 20 mL of fuming (30%) sulfuric acid under an inert atmosphere.   Dissolution of triphenylphosphine was noted after a few minutes, resulting in a yellow solution. The reactor was heated by a hot water bath at 60 ° C. and left under stirring for 1 hour . The acid solution was first cooled and then added dropwise to 20 mL of demineralized water using a dropping funnel. It was poured under the elementary flow.   This solution was neutralized with 30% NaOH. During this process, crystallization of the heterogeneous solid Was observed. The crystallization was completed by cooling to 0-5 ° C. The product ( The sulfonated phosphine mixed with sodium sulfate) was recovered.   The solid was recrystallized from water to remove sodium sulfate. Decompress the separated crystals Dry under (20 mmHg; 35 ° C; 8 hours). The resulting sulfonated phosphine The yield of the resin was about 80%.Example 2 Reduction in homogeneous phase 500 mL of isopropyl alcohol and 20 g of avermectin (92% B_1aIsomer and 5% B_1bIsomer) and 750 mg of [RhCl (COD )]_Two(COD = 1,5-cyclooctadiene) (this is Aldrich, co.) deNo. 22,795-1) and 3.37 g of sulfonation prepared in Example 1 A mixture comprising phosphine (molar ratio phosphine / [RhCl (COD)])_Two= 6: 1) to a Pearl 4522M autoclave with a 1 L stainless steel reactor Was filled.   The autoclave is sealed, 3 times with nitrogen and 2 times with hydrogen , And then the hydrogen pressure was increased to 7 atm. Start stirring and gradually increase the temperature To 55 ° C.   After a 7-hour reaction, HPLC analysis showed the disappearance of avermectin and the Lumectin (B_1aAnd B_1bConversion to isomers) with greater than 98% yield, And the appearance of small amounts of reaction by-products.   Maintain the reaction mixture under nitrogen atmosphere for 12 hours with slow stirring at 0-5 ° C did. Filtration and washing were performed with isopropanol. Has a yellow-orange color, mainly anti- 2.45 g of a solid made of a catalytic material was recovered.   The resulting alcohol solution is concentrated by distillation until an oil is obtained, Dissolved in mL of toluene. 0.96 g of thiourea are refluxed for 8 hours It was added while maintaining. Cooling to 0-5 ° C and maintaining this temperature for about 1 hour And filtration. The solution was concentrated and the resulting oil was added to 80 mL of ethanol. Was dissolved. 200 mL of formamide and 40 mL of water at 45 ° C. into solution Was added. Cooling and maintenance at room temperature for 12 hours was performed. Filtration and 3: 1 water Washing with ethanol mixture and dissolving of the isolated solid in 80 mL of ethanol Was done. Add 80 mL of 45 ° C. water to the solution, cool, and maintain at room temperature. Filtered overnight and washed with a 1: 1 mixture of water in ethanol. 1 7 g of the finished product characterized by the following analytical technique were isolated.   Mass (EI, 90 eV for actual ionization, 0.5 mA, 3 kV for acceleration, starting T25 0 ° C, probe T 0.5 ° C / s).   Main signal (m / z): 874, 856, 730, 712, 586, 568, 550, 307, 293, 195, 145 and 113.   UV (methanol)   The signal has an absolute maximum at 244.7 nm.   This type of data is consistent with data reported in publications for ivermectin. : Analytical profiles of drug subs tanks (1988), vol. 17, pp. 155-184.Example 3 Reduction in homogeneous phase   1.5 L of isopropyl alcohol and 12 g of avermectin (93% B_1a Isomer and 4.5% B_1b0.17 g Aldrich (consisting of isomers) [RhCl (COD)]_TwoAnd 0.5 manufactured by Basf 3 g of triphenylphosphine (phosphine / [RhCl (COD)]_TwoMole of Ratio = 3: 1) with the 2 L stainless steel already used in the test described in Example 2. The autoclave having a stainless steel reactor was charged. Close the autoclave and place under nitrogen Condition three times with hydrogen and then twice with hydrogen, then 7 cycles under hydrogen pressure Pressure. Stirring was started and the temperature was gradually raised to 50 ° C. After 7 hours reaction, HP LC analysis showed the disappearance of avermectin and its Vermectin (B_1aAnd B_1bTo 98% yield, with a small amount of The formation of by-products was also observed. Reaction mixture according to the techniques described in the above examples The product isolated from was characterized by recording NMR, UV and mass spectra . The data obtained from the analysis of this sample is the data reported at the end of the above example. And overlap with data described in publications.Example 4 Reduction in homogeneous phase   1.5 L toluene and 16 g avermectin (92% B_1aIsomer and 5 % B_1b(Consisting of isomers) and 75 mg made by Aldrich [ RhCl (COD)]_TwoAnd 240mg of Trifeni made by Basf Luphosphine (phosphine / [RhCl (COD)]_TwoOf 6: 1) and The autoclave used in the test described in Example 3 was filled. Haute The lave was sealed and conditioned first under nitrogen and then under hydrogen. The reaction mixture was stirred at 65 ° C. and 7 atm of hydrogen for 7 hours with vigorous stirring. The partial pressure was maintained. The course of the reaction was followed by HPLC analysis. This analysis shows that the conversion yield to ivermectin is greater than 95% and that It indicated that there was a small amount of reaction by-product appearance. According to the technique described in the second embodiment. Characterize isolated reaction products by recording NMR, UV and mass spectra Was. The resulting data overlaps with the data inserted after Example 2 and further Data consistent with the data reported in the publication.   Furthermore, the reduction process has essentially unchanged results when water is added to the reaction mixture. Indicated.Example 5 Reduction in homogeneous phase   600 mL of isopropyl alcohol and 12 g of avermectin (93% B_1a Isomer and 4.5% B_1bIsomer) and 450 mg [RhCl (C OD)]_TwoAnd 2 g of sulfonated phosphine prepared by the method disclosed in Example 1. Phosphine / [RhCl (COD)]_TwoOf the formula = 6: 1) The autocove already used in the test described in 2 was filled. This oak The valve is sealed and conditioned first under nitrogen and then under hydrogen, then hydrogen pressure The pressure was increased to 7 atm. Stirring was started and the temperature was gradually raised to 60 ° C. 6 hours anti After the reaction, HPLC analysis showed the disappearance of avermectin and then ivermectin ( B_1aAnd B_1bTo the isomer). A small amount of anti The formation of by-products was also observed. According to the technique described in Example 2, the reaction product was The released product was characterized by recording NMR, UV and mass spectra. Trial The data obtained from the analysis of the feeds overlapped the data reported at the end of Example 2. And further overlap with the data described in the publication.Example 6 Reduction in homogeneous phase   The experimental procedure described in Example 2 was followed, but with 750 mg of [RhCl (COD) ]_TwoAnd 6.74 g of sulfonated phosphine (phosphine / [RhCl (COD) ]_TwoOf avermectin in a 40% yield. Conversion to lumectin was obtained.Example 7 Reduction in homogeneous phase without phosphine   The experimental procedure described in Example 2 was repeated and 750 mg of [RhCl (COD)]_Two Only phosphine was charged. About 50% Conversion of avermectin to ivermectin in a yield of was obtained. HPLC min The precipitation showed the presence of large amounts (greater than 15%) of decomposition products.Example 8 Reduction in homogeneous phase for catalyst recycling   The catalyst recovered in Example 2 was subjected to a reduction reaction in which the procedure described in Example 2 was repeated. 0.26 g of [RhCl (COD)]_TwoAnd 1.18g Of phosphine (phosphine / [RhCl (C OD)]_TwoAnd the resulting molar ratio = 3: 1) 35% of the medium was remixed. The yield of the reaction is comparable to that obtained in Example 2. (Greater than 98%).Example 9 Reduction in heterogeneous phase   3.5 g of avermectin (93% B_1aIsomer and 4.5% B_1bIsomer Consisting of) and 130 mg (98%) of [RhCl (COD)]_TwoAnd 350 mL The solution obtained by dissolving in toluene was first charged and then described in Example 1. 0.59 g of sulfonated phosphine (phosphine / phosphine / [RhCl (COD)]_TwoRatio = 6: 1) and 515 mg of tetrabutylammonium bromide And a solution obtained by dissolving the same in 85 mL of water was subjected to the test described in Example 2. The used autoclave was filled. Seal the autoclave and A first flush with nitrogen and a second flush with hydrogen. Intense heterogeneous mixture Maintained at 65 ° C. and 7 atmospheres hydrogen pressure with good stirring for 7 hours. Excessive reaction The process was followed by HPLC analysis. Analysis showed that the yield of conversion to ivermectin was 98 % And the ratio in the homogeneous phase to the method of the invention (see Example 2) That there was a much reduced amount of reaction by-products (equal to about half). Indicated. In addition, this type of reduction was performed using Wilkinson's catalyst in US-4.   Even the method of 199 569 can be observed.   At the end of the reaction, the toluene solution obtained after separating the heterogeneous mixture is distilled off. While concentrating, the obtained oil was dissolved in 14 mL of ethanol.   The resulting aqueous phase containing the catalyst is separated and, if necessary, recycled for subsequent reduction. Can cycle.   35 mL of formamide and 7 mL of water were added at 45 ° C to an oil. Added to the ethanol solution. Cooling, overnight maintenance at room temperature, filtration, and the like The solid was washed with a 25% ethanol solution in water. Crude Dissolve the product in 13 mL of ethanol, add 13 mL of water to the 45 ° C. solution, Cool, maintain at room temperature for 12 hours, filter, then water 1: Washing with one mixed solution was performed. Characterized by UV, NMR and mass spectra 3 g of the finished product were isolated. The data obtained was reported at the end of Example 2. Overlap with data.Example 10 Reduction in heterogeneous phase   4 g of avermectin (92% B_1aIsomer and 5% B_1bWith isomer ) And 150 mg of [RhCl (COD)]_TwoAnd dissolved in 600 mL of toluene The resulting solution is first charged and then 0.68 g of the method described in Example 1 (Phosphine / [RhCl (COD)])_Two Ratio = 6: 1) and 0.79 g of tetrabutylammonium bromide in 150 mL A solution obtained by dissolving in water, Pearl 4522 having a 1 L stainless steel reactor. For M autoclave Filled. The autoclave is sealed and first nitrogen and then hydrogen Was carried out. The heterogeneous mixture was stirred at 60 ° C. and 6 The pressure was maintained under a hydrogen pressure for 9 hours. Follow the reaction by HPLC analysis did. The analysis showed that the yield of the reaction was quantitative and the appearance of reduced amounts of reaction by-products Was present. Reaction products isolated by the techniques described in the previous examples. The material was characterized by recording NMR, UV and mass spectra. Data obtained Overlaps with the data inserted after Example 2 and is described in the publication. Match withExample 11 Reduction in heterogeneous phase   The experimental procedure described in Example 9 was followed, but with 130 mg of [RhCl (COD) ]_TwoAnd 0.3 g of sulfonated phosphine (1 to 3 [RhCl (COD)]_Two/ E (Equal to the molar ratio of sphines). From avermectin to ivermectin Was obtained in 85% yield. The amount of decomposition products was negligible.Example 12 Reduction in heterogeneous phase without phase transfer agent   The procedure of Example 9 was repeated in the absence of a quaternary ammonium salt. Reaction yield is 7 It was 0%.Example 13 Reduction in heterogeneous phase recycling catalyst   3.5 g of avermectin (92% B_1aIsomer and 5% B_1bFrom isomers Is dissolved in 350 mL of toluene, and the resulting solution is charged first. The aqueous phase isolated at the end of the reaction described in Example 9 was already used in Example 2. The autoclave was filled. The resulting mixture is heated at 65 ° C. for 7 hours. The reaction was carried out under atmospheric hydrogen pressure. Some experimental data are reported in the table below, and are shown for reduction with (known) Wilkinson's catalyst. The respective considerations are presented for comparison purposes. Return performed using Wilkinson's catalyst Original data was extracted from Example 11 of US Pat. No. 4,199,569. Note¹Wilkinson [RhCl (PAr)_Three] (Known)Example 14 (Recovery of ivermectin obtained from reduction performed in homogeneous phase)   The alcohol solution resulting from the conversion of avermectin performed in Example 3 was Was concentrated until a product was obtained. The obtained oil was dissolved in 72 mL of 20% aqueous ethanol. The resulting solution was dissolved in a 600 mL tree Packed in a column with a panel of Fat SP850. Most concentrated fraction Is eluted with an aqueous-ethanolic solution having a water content of 20%, Evaporate and recover the final product according to the procedure described in Example 2, but with thiol Collected by bypassing the step containing urea.Example 15 (Recovery of ivermectin obtained from reduction performed in heterogeneous phase)   Tolue obtained after separating off the heterogeneous mixture at the end of the reaction described in Example 9. The solution is concentrated by distillation and the oil obtained is reduced to 20 m with a water content of 12%. L of water-ethanol solution. This solution is manufactured by Mitsubishi A column having a panel of 230 mL of resin SP825 was packed. Darkest Collect the condensed fraction, which contains ethanol The aqueous solution is eluted with a solvent mixture having the same composition and then dried by concentration. I let it. The final product is then recovered according to the procedure described in Example 9, first of all Crystals from a ternary mixture of water-formamide-ethanol and water-ethanol 2 A second crystallization from the component mixture was performed.

────────────────────────────────────────────────── ─── Continuation of front page    (72) Inventors Rossi, Aretzsandro             Italy, i-20068 Pesciera Bo             Romeo, Via Matsuteotsutei, 55/7 (72) Inventors Teratusan, Daniele             Italy, I-20049 ・ Concoretsu,             Via Don Bosco, 1 (72) Inventor Bernasconi, Ermanno             Italy-21040 Karono Baresi             No, Via Cuazimod, 7 (72) Inventor Terreros, Pilar             Spain, A28002 Madrid, Sa             Baleta, 54, 2 ・ a (72) Inventor Salt, Francisco             Spain, A-28223 Madrid, Po             Cerro, Calle Abrejo, Numero 33-Sef             Nd se

Claims (1)

[Claims] 1. A dimer of rhodium chloride 1,5-cyclooctadiene and the following formula: [P (ArXn ₁ ) (ArXn ₂ ) (ArXn ₃ )] · nNa wherein Ar is an aryl group and X is a sulfone group SO ₃ And each of n ₁ , n ₂ and n ₃ independently is equal to 0 or 1 and n ₁ + n ₂ + n ₃ is equal to n which is an integer greater than or equal to 0. Reducing avermectin in the presence of a catalyst formed in situ by the reaction between the dimer of rhodium chloride 1,5-cyclooctadiene and the phosphine in a molar ratio of 1: 3 to 1 : 12, preferably 1: 6, a method for producing ivermectin. 2. The method according to claim 1, wherein the reaction is carried out in both a homogeneous phase and a heterogeneous phase in the presence of a solvent. 3. In the homogeneous phase, when n is greater than or equal to 1, use is made of an alcoholic organic solvent or an aliphatic chlorinated or aliphatic esterified solvent selected from linear or branched C ₁ -C ₄ alkyl alcohols. And the following steps: (a) recovering the catalyst from the solution containing the reaction product by cooling and filtration; (b) recovering ivermectin from the resulting night liquor by known techniques; 3. A process according to claim 2 including the step of c) recycling the recovered catalyst after its full regeneration, for subsequent reduction. 4. 3. The method according to claim 2, wherein in the homogeneous phase, when n is equal to 0, the method comprises the use of an aromatic, alcoholic, aliphatic, chlorinated or aliphatic esterified organic solvent. 5. Use of an aromatic, aliphatic, chlorinated or aliphatic esterified organic solvent, preferably toluene and a solvent immiscible with said solvent, preferably water, when n is greater than or equal to 1 in the heterogeneous phase 3. The method according to claim 2, comprising: 6. The method of claim 5, wherein the organic phase initially comprises avermectin and a dimer of rhodium chloride 1,5-cyclooctadiene, and the immiscible phase comprises phosphine and optionally a phase transfer agent. 7. (Α) separating each layer; (β) recovering the ivermectin from the organic phase according to known techniques; and optionally (γ) recycling the catalyst to a phase immiscible with the organic phase. Item 7. The method according to Item 5 or 6. 8. The method according to any one of claims 1 to 3 and 5 to 7, wherein the phosphine is sodium diphenylphosphinobenzene methanesulfonate. 9. 9. The process according to claim 1, wherein the reduction is carried out at a temperature of from 20 to 70 [deg.] C., preferably at from 45 to 65 [deg.] C. and at a pressure of from 4 to 8 atm, preferably from 5 to 7 atm. 10. The ivermectin recovery in either the homogeneous or heterogeneous phase can be accomplished by first concentrating the resulting ivermectin solution and then diluting the resulting substrate with an aqueous-alcoholic solvent mixture (where the water in the premix is 10-30% water). And the alcohol is a linear or branched C ₁ -C ₄ alkyl alcohol) and is eluted with an adsorbent nonionic resin having a styrene-divinylbenzene matrix and the resin / substrate ratio is 1 g of ivermectin 10. The method according to any one of claims 1 to 9, wherein the method ranges from 5 to 80 mL per bottle.