KR20000065035A - Method of Making Ivermectin - Google Patents

Abstract

The present invention relates to a process for the production of ivermectin by reducing avermectin, which yields a final product with high purity and high yields.

Description

Method of Making Ivermectin

The present invention relates to a method for preparing ivermectin by reducing avermectin.

Ivermectin (22,23-dihydroavermectin) exhibits parasitic killing activity (as insecticidal, in vitro parasitic killing agents, insecticides and tick repellents) and is currently used in the treatment of humans or in veterinary or agriculture.

Selective reduction of avermectin to ivermectin is known and is performed in situ using a Wilkinson catalyst consisting of a complex salt of rhodium (I) chloride and triphenylphosphine trimolecules.

The reaction described in U.S. Patent No. 4 199 569 consists of only cis-disubstituted double bonds among the five unsaturateds present in the molecule, allowing the stereo-specific hydrogenation of 22,23 double bonds with low steric hindrance do.

There is a problem in treating the reaction product according to known methods to recover ivermectin. It is necessary to separate the ivermectin by first distilling off the solvent, usually toluene, and then recovering the solvent and obtaining a solution from it, crystallizing it by the addition of an insoluble material, generally water, until an oily residue is obtained. have. Primary precipitation of ivermectin is carried out in a medium containing a Wilkinson catalyst, whereby the final product contains a significant amount of rhodium (100-200 ppm) as impurities.

The reaction product in various modification methods (described in US Pat. No. 4413118) for increasing the recovery of rhodium and decreasing its content in ivermectin is a compound having a carbon-sulfur double bond in an organic solvent, preferably at reflux. Is treated with thiourea to separate the rhodium complex salt, followed by direct metal recovery and preparation of a fresh Wilkinson catalyst. A large amount of thiourea (2-12 mol / mol rhodium), which is known to have reactivity showing significant ecological and environmental disadvantages, is still used in this treatment.

Now, a reaction between a dimer of rhodium chloride 1,5-cyclooctadiene and at least one phosphine having the formula (I), which is an object of the present invention, wherein the dimer of rhodium chloride 1,5-cyclooctadiene and one or more The molar ratio between phosphines is between 1: 3 and 1:12, preferably 1: 6), revealing a process for preparing ivermectin, including reducing avermectin in the presence of a catalyst prepared in situ. lost.

[P (ArXn ₁ ) (ArXn ₂ ) (ArXn ₃ )] · nNa

In the above formula,

Ar is an aryl group, X is a sulfonic acid group SO ₃ , n ₁ , n ₂ and n ₃ are independently 0 or 1 and n ₁ + n ₂ + n ₃ is equal to n, an integer of 0 or greater.

Preferably Ar is phenyl group C ₆ H _5- .

The process of the invention can be carried out by reduction in the presence of a solvent in both homo and hetero phases.

The process of the invention is homogeneous, in the case of phosphine compounds of formula (I) wherein n is at least ₁ , an alcoholic organic solvent selected from straight or branched C ₁ -C ₄ alkyl alcohols (e.g. methanol, ethanol, isopropanol, especially isopropanol) Or using an aliphatic chlorinated solvent such as methylene chloride or an aliphatic esterified solvent such as ethyl acetate,

(a) cooling the solution containing the reaction product and filtering to recover the catalyst;

(b) recovering ivermectin from the solution obtained using known techniques; And optionally

(c) recycling the recovered catalyst to its subsequent reduction process after appropriate recovery.

In fact, most of the catalysts which have been subjected to the above-described steps are recovered by filtration of the precipitate precipitated by cooling from the reaction product; Suitably recovered catalyst is optionally reused for subsequent reduction processes. Ivermectin is finally separated from the alcohol solution by known techniques.

For example, the recovery of ivermectin is described in US Pat. No. 4, 199 569 and US Pat. No. 4,413,118 under reflux of the resulting ivermectin solution in an organic solvent, generally toluene, under reflux. This is accomplished by treatment with a significantly smaller amount of thiourea (2-12 mol / mol rhodium) relative to the amount of thiourea described.

The process of the invention when phosphine of the above formula where n = 0 is used comprises the use of aromatic, alcoholic, aliphatic chlorinated or aliphatic esterified organic solvents, preferably toluene, isopanol, methylene chloride or ethyl acetate do.

The method of the present invention comprises heterologous sulphonated phosphines; Aromatic, aliphatic chlorinated or aliphatic esterified organic solvents, preferably toluene; And using a solvent which is incompatible with the organic solvent, preferably water: first the organic phase comprises a dimer of avermectin and rhodium chloride 1,5-cyclooctadiene, wherein the incompatible phase is a sulfonated force Phase-transfer materials, in particular quaternary ammonium salts and alkyl sulfonates, which include fins and may optionally be selected from compounds commonly used in the art, preferably the phase-transfer material is tetrabutylammonium bromide.

The process of the present invention further comprises separating the (α) phase from the heterologous phase; (β) ivermectin is recovered from the organic phase according to known techniques; Optionally (γ) reusing the catalyst in a phase that is incompatible with the organic phase.

As described, for example, in US Pat. No. 4, 199 569 and US Pat. No. 4,413,118, the organic phase containing ivermectin obtained is concentrated and treated with a mixture of formamide and water and then cooled Ivermectin can be recovered in heterogeneous ways by separating the final product by filtration washing.

Reduction in homogeneous and heterophasic phases is carried out at a temperature of 20 to 70 ° C., preferably 45 to 65 ° C., and a pressure of 4 to 8 atm, preferably 5 to 7 atm.

The process of the present invention selectively reduces the avermectin to obtain high purity and high yield of ivermectin, the resulting by-products are significantly lower, and further use 10 times less rhodium than used in known methods. do.

The most preferred sulfonated phosphine according to the invention is sodium diphenyl phosphinobenzene metasulfonate.

When sulfonated phosphines are used in place of Wilkinson's complex salts, the catalytic complex salts of the process of the present invention include a class of catalysts used in oxo synthesis known in the literature, for example in the synthesis of aldehydes starting from olefins.

In addition, these catalysts are particularly water soluble and can therefore be used in the dual phase reaction of olefins. Its preparation and use is described in J. Chatt et al., J. Chem Soc. 1958, 276, 88; AF Borowsky et al., Nouveau Journal de chemie, 1977, vol. 2, n. 2, p. 137-144; F. Joo and MT Beck, Reac. Kin. And Cat. Letters, 1975, vol. 2, n. 3, 257-263; E. Kuntz, Chemtech. Sept. 1987).

The advantage obtained with this sulfonated catalyst system lies in the easy separation and reuse of the catalyst and in fact it is possible to remove the reaction product without modifying or damaging the catalyst, thus making it possible to use expensive catalysts such as rhodium. I think it has more remarkable validity than when using.

A further advantage that can be obtained by carrying out the process of the invention on heterogeneous phases is the possibility of significantly lowering the impurity compared to the process of the invention carried out on homogeneous phases and to processes using (known) Wilkinson catalysts.

A further subject matter of the present invention is the recovery of ivermectin in both homo and hetero phases, concentrating the first obtained ivermectin solution and then the obtained concentrate on water on an adsorptive nonionic resin with styrene-divinyl benzene matrix. In an aqueous-alcohol solvent mixture where 10 to 30% and the alcohol is a straight or branched C ₁ -C ₄ alkyl alcohol, wherein the resin / substrate ratio is a resin / ivermectin 5 to 80 ml ratio per gram of ivermectin. By elution).

Therefore, the recovery of ivermectin according to the present invention is preferably carried out on the adsorbed nonionic resin with styrene-divinyl benzene matrix (HP and SP, manufactured by Mitsubishi Chemical) E) by eluting with an aqueous-alcohol solvent mixture where the most preferred alcohols are methanol, ethanol and isofpanol. The obtained ivermectin elutes with the mobile phase, while rhodium stays bound to the stationary phase.

The ivermectin recovery method according to a preferred embodiment of the present invention described above makes it possible to obtain the highest quality final product in high yields of 85 to 90%, with a low rhodium content. This recovery method also lowers the inherent impurity of the method.

Furthermore, the recovery method according to the last aspect of the invention described above has the advantage of avoiding the use of thiourea.

The following examples illustrate the invention but are not limited thereto.

Example 1

Preparation of Sulfonated Phosphine

Sulfonated phosphines are prepared by the methods described in J. Chem. Soc. 1958, 276, 88. 10 g of triphenyl phosphine are carefully added to 20 ml of pyrolysis (30%) oleum in an inert atmosphere.

After a few minutes the dissolution of triphenylphosphine begins, and the solution is yellowish. The reactor is heated in a 60 ° C. hot water bath and left under stirring for 1 hour. The acid solution is first cooled and then added to 200 ml of deionized water under a stream of nitrogen using a dropping funnel.

This solution is neutralized with 30% NaOH. The heterogeneous solid is crystallized during this step. Cool to 0-5 ° C. to complete crystallization. Filtration recovers the product (sulfonated phosphine mixed with sodium sulfate).

The solid is recrystallized from water to remove sodium sulfate. The separated crystals are dried under vacuum (20 mm Hg; 35 ° C .; 8 hours). The yield of sulfonated phosphine obtained is about 80%.

Example 2

Reduction in homogeneous phase

500 ml of isopropyl alcohol, and 20 g of avermectin (92% of B _1a isomer and 5% of B _1b isomer), [RhCl (COD)] ₂ (COD = 1, 5-cyclooctadiene) (manufacturer: Aldrich, code 22,795 -1) A mixture comprising 750 mg and 3.37 g of sulfonated phosphine prepared in Example 1 is placed in a Parr 4522M sterilizer with a 1 L stainless steel reactor.

The sterilizer is closed, washed three times with nitrogen and twice with hydrogen and then pressurized to 7 atm of hydrogen pressure. Start the stirring and allow the temperature to gradually rise to 55 ° C.

After 7 hours of reaction, HPLC analysis showed that avermectin disappeared and showed conversion to ivermectin (B _1a and B _1b isomers) with a yield of at least 98% and a low amount of reaction byproducts.

The reaction mixture is kept at 0-5 [deg.] C. for 12 hours under a nitrogen atmosphere with gentle stirring. Filtration and washing with isopropanol recovers 2.45 g of an orange solid consisting primarily of the catalyst catalyzing the reaction.

The resulting alcohol solution is concentrated by evaporation to give an oil and dissolved in 750 ml of toluene. 0.96 g of thiourea is added while maintaining reflux for 8 hours. Cool to 0-5 ° C. and hold at this temperature for about 1 hour and filter. The oil obtained by concentrating the solution is dissolved in 80 ml of ethanol. 200 ml of formamide and 40 ml of water are added to the solution at 45 ° C. Cool and keep at room temperature for 12 hours. Filter and wash with water-ethanol 3: 1 mixture and dissolve the separated solid in 80 ml of ethanol. 80 ml of water was added to the solution at 45 ° C., cooled, filtered while maintaining room temperature overnight and washed with an ethanol-water 1: 1 mixture. Analytical techniques separate 17 g of final product having the following characteristics.

¹ H-NMR (CDCl ₃ , 300 MHz)

0.80 ppm (d, Me-24); 0.87 ppm (d, Me-26); 0.93 ppm (t, Me-28); 1.18 ppm (d, Me-12); 1.27 ppm (d, Me-5 '); 1.30 ppm (d, Me-5 "); 1.51 ppm (s, Me-14); 1.78 ppm ('d', H-18eq); 1.88 ppm (s, Me-4); 1.99 ppm (dd, H- 20eq); 2.52 ppm (m, H-12); 3.17 ppm (t, H-4 "); 3.42 ppm (s, OCH ₃ ); 3.44 ppm (s, OCH ₃ ); 3.95 ppm (s, H-13); 3.98 ppm (d, H-6); 4.17 ppm (s, OH); 4.30 ppm (d, H-5); 4.69 ppm (m, 2 H-8a); 4.78 ppm (d, H-1 '); 4.98 ppm [d, H-15 (CH =)]; 5.34 ppm (m, H-19); 5.40 ppm (d, H-1 "); 5.43 ppm [s, H-3 (= CH-)]; 5.74 ppm [m, H-10e H-11 (HC = CH-)]; 5.87 ppm [d , H-9 (= CH-)].

¹³ C-NMR (CDCl ₃ , 300 MHz)

173.8 ppm, C (1); 139.6 ppm, C (8); 138.0 ppm C (11); 137.8 ppm C (4); 135.0 ppm C (14); 124.7 ppm C (10); 120.4 ppm, C (9); 118.3 ppm, C (3); 98.5 ppm, C (1 ″); 97.5 ppm, C (21); 94.8 ppm, (C1 ′); 81.8 ppm, C (13); 80.5 ppm, C (4); 80.4 ppm, C (7); 79.4 ppm, C (6), 79.3 ppm, C (3 '), 78.2 ppm, C (3 "); 76.5 ppm C (25); 76.1 ppm, C (4 "), 68.7 ppm, C (5 "); 68.4 ppm, C (17 o 19); 68.1 ppm, C (8a); 67.7 ppm, C (5); 67.2 ppm, C (5 ") & C (17 o 19); 56.5 ppm, OCH ₃ ; 56.4 ppm, OCH ₃ ; 45.7 ppm, C (2); 41.2 ppm, C (20); 39.7 ppm, C (12 36.9 ppm, C (16); 35.7 ppm, C (26); 34.5 ppm; 34.2 ppm, C (18); C (2 '), C (2 "); 34.1 ppm; 31.2 ppm, C (24); 28.1 ppm, C (23); 27.3 ppm, C (27); 20.2 ppm, C (12a); 19.9 ppm, C (4a); 18.4 ppm, C (6 ″); 17.7 ppm, C (6 ′); 17.4 ppm, C (24a); 15.1 ppm, C (14a); 12.4 ppm, C (26a); 12.1 ppm, C (28).

Mass (EI, practical ionization 90 eV, 0.5 mA, 3 kV acceleration, onset temperature 250 ° C, probe T 0.5 ° C / s)

Main signals (m / z): 874, 856, 730, 712, 586, 568, 550, 307, 293, 195, 145 and 113

UV (methanol)

The signal is absolute maximum at 244.7 nm.

This data confirms what is described in the literature on ivermectin (Analytical Profiles of drug substances, 1988, Vol. 17, p. 155-184).

Example 3

Reduction in homogeneous phase

1.5 L of isopropyl alcohol, 12 g of avermectin (93% of B _1a isomer and 4.5% of B _1b isomer), 0.17 g of [RhCl (COD)] ₂ (manufactured by Aldrich) and triphenylphosphine prepared in Example 2 A molar ratio of phosphine / [RhCl (COD)] ₂ = 3: 1) (manufacturer: Basf) was added to the sterilizer already used in Example 2 with a 2 L stainless steel reactor. The sterilizer is closed and adjusted three times under nitrogen and twice under hydrogen and then pressurized to 7 atm of hydrogen pressure. Start the stirring and allow the temperature to gradually rise to 55 ° C. After 7 hours of reaction, HPLC analysis showed that avermectin disappeared and showed conversion of ivermectin (B _1a and B _1b isomers) with a yield of at least 98% and a small amount of reaction byproducts. The product isolated from the reaction mixture according to the technique described in the above examples is characterized by the recorded NMR, UV and mass spectra, and the data obtained by analysis of the samples are the same as the data inserted in Example 2 above and described in the literature. Corresponds to them.

Example 4

Reduction in homogeneous phase

1.5 liters of toluene, 16 g of avermectin (92% of B _1a isomer and 5% of B _1b isomer), 750 mg of [RhCl (COD)] ₂ (manufactured by Aldrich) and triphenylphosphine (phosphine / [RhCl (COD)] Molar ratio of ₂ = 6: 1) (manufacturer: Basf) 240 mg is placed in a sterilizer already used in Example 3. The sterilizer is closed and adjusted first under nitrogen and then under hydrogen. Rapid stirring is maintained at 65 ° C. for 7 hours under a partial pressure of hydrogen of 7 atm. The reaction is then analyzed by HPLC. Analysis yields conversion of ivermectin above 95% and low reaction byproducts. The reaction product isolated according to the technique described in Example 2 above was characterized by the recorded NMR, UV and mass spectra. The data obtained are the same as the data inserted after Example 2 and correspond to those described in the literature.

In addition, the reduction reaction results in basically unchanged even when water is added to the reaction mixture.

Example 5

Reduction in homogeneous phase

600 ml of isopropyl alcohol, 12 g of avermectin (93% of B _1a isomer and 4.5% of B _1b isomer), 450 mg of [RhCl (COD)] ₂ and ₂ g of sulfonated phosphine prepared in Example 1 (phosphine / [ RhCl (COD)] ₂ molar ratio = 6: 1) (manufacturer: Basf) is placed in the sterilizer already used in Example 2. The sterilizer is closed and first adjusted under nitrogen, then under hydrogen, and then pressurized to 7 atm of hydrogen pressure. The temperature is gradually brought to 60 ° C. while stirring. HPLC analysis after 6 hours of reaction showed avermectin disappearing and conversion to ivermectin (B _1a and B _1b isomers) with large yields. In addition, adaptive amounts of reaction byproducts are formed. The product isolated from the reaction mixture according to the technique described in Example 2 above was characterized by the recorded NMR, UV and mass spectra, and the data obtained were the same as the data inserted after Example 2, and those described in the literature. Corresponds.

Example 6

Reduction in homogeneous phase

Into the experimental method described in Example 2, 750 mg of [RhCl (COD)] ₂ and sulfonated phosphine (molar ratio of phosphine / [RhCl (COD)] ₂ = 12: 1) were added to ivermectin in avermectin. A conversion with 40% yield to is obtained.

Example 7

Reduction on morphine without phosphine

The experimental method described in Example 2 is repeated with only 750 mg of [RhCl (COD)] ₂ without phosphine. A conversion with 50% yield from avermectin to ivermectin is obtained. HPLC analysis shows that large amounts of decomposition products (15% or more) are present.

Example 8

Reduction in homogeneous phase reusing catalyst

The catalyst recovered in Example 2 was reused in a reduction reaction while repeating the method described in Example 2 and 0.26 g of [RhCl (COD)] ₂ and 1.18 g (phosphine) obtained as described in Example 1 The obtained molar ratio of / [RhCl (COD)] ₂ = 3: 1) was added again to combine 35% of the spent catalysts. The reaction yield is similar to that obtained in Example 2 (at least 98%).

Example 9

Reduction in heterogeneous phase

A solution obtained by dissolving 3.5 g of avermectin (93% of B _1a isomer and 4.5% of B _1b isomer) and 130 mg of (98%) [RhCl (COD)] _{2 in} 350 ml of toluene was added first, followed by Example 1 515 mg of tetrabutylammonium bromide in 85 ml of water and a solution obtained by dissolving 0.59 g of sulfonated phosphine (molar ratio of phosphine / [RhCl (COD)] ₂ = 6: 1) prepared according to the procedure described in It is placed in a sterilizer already used in Example 2. The sterilizer is closed and washed first under nitrogen and then under hydrogen. The heterogeneous mixture is kept stirring rapidly at 65 ° C. for 7 hours under hydrogen pressure. Then HPLC analysis. The analysis shows that the yield of conversion to ivermectin is at least 98%, and that the reaction by-products are smaller (equivalent to half) relative to the method of the invention on homogeneous (see Example 2). In addition, less is observed even in the method of US Pat. No. 4, 199 569, carried out using a Wilkinson catalyst.

At the end of the reaction, the heterogeneous mixture is separated and the toluene solution obtained is evaporated to concentration and the oil obtained is dissolved in 14 ml of ethanol.

The resulting aqueous phase containing the catalyst can be separated off and optionally reused in continuous reduction.

35 ml of formamide and 7 ml of water are added to an ethanol solution in 45 ° C. oil. Cool and filter overnight while keeping at room temperature and wash the solid obtained with a 25% solution of ethanol in water. The crude product is dissolved in 13 ml of ethanol, 13 ml of water is added to the solution at 45 ° C., cooled and filtered while maintaining at room temperature for 12 hours and washed with a 1: 1 mixture of water in ethanol. Separate 3 g of final product with UV, NMR and fine spectral characteristics. The obtained data is the same as the data inserted below in Example 2.

Example 10

Reduction in heterogeneous phase

A solution obtained by dissolving 4 g of avermectin (92% of B _1a isomer and 5% of B _1b isomer) and 150 mg of [RhCl (COD)] _{2 in} 600 ml of toluene was first added, followed by the method described in Example 1. A solution obtained by dissolving 0.68 g of sulfonated phosphine (molar ratio of phosphine / [RhCl (COD)] ₂ = 6: 1) prepared according to the present invention, and 0.79 g of tetrabutylammonium bromide in 150 mL of water were prepared in a 1 L stainless steel reactor. Put in the Parr 4522 M sterilizer. The sterilizer is closed and washed first under nitrogen and then under hydrogen. The heterogeneous mixture is kept stirring rapidly at 60 ° C. for 9 hours under 6 atm hydrogen pressure. Then HPLC analysis. The analysis shows a high yield of reactions and low amounts of reaction by-products. Reaction products isolated according to the techniques described in the Examples below are characterized by the recorded NMR, UV and mass spectra. The data obtained are identical to those inserted in Example 2 and below, and correspond to those recorded in the literature.

Example 11

Reduction in heterogeneous phase

Example 9 according to the method described in [RhCl (COD)] ₂ 130㎎ and phosphine / [RhCl (COD)] ₂ molar ratio of 1: 3 filled with a sulfonated phosphine 0.3g. Conversion of avermectin to ivermectin is obtained in a yield of 85%. The amount of degraded product is negligible.

Example 12

Reduction in dissimilar phase without phase change material

The method of Example 9 is repeated in the absence of quaternary ammonium salts and the yield of the reaction is 70%.

Example 13

Reduction in Heterogeneous Phases Reusing Catalysts

The solution obtained by dissolving 3.5 g of avermectin (92% of B _1a isomer and 5% of B _1b isomer) in 350 ml of toluene was first placed in the sterilizer already used in Example 2 and then the end of the reaction described in Example 9. Into the separated aqueous phase. The resulting mixture was reacted at 65 ° C. for 7 hours under 7 atm hydrogen pressure.

Some experimental data is shown in Table 1 below, whereby it is illustrated for purposes of comparison in terms of reduction with (known) Wilkinson catalysts, and the data concerning reduction carried out using Wilkinson catalysts are described in the Examples of US Pat. No. 4 199 569. 11 is shown.

menstruum Prize yield(%) Isopropanol (Example 2) the same kind > 98 Toluene / H ₂ O (Example 9) Heterogeneous 98-99 Toluene ¹ the same kind > 98 ¹ Reduction with Wilkinson [RhCl (PAr) ₃ ]

Example 14 (Recovery of ivermectin obtained from reduction performed on homogenous phase)

The alcohol solution obtained from the conversion of avermectin carried out in Example 3 is concentrated to give an oil. The obtained oil is dissolved in 72 ml of 20% aqueous ethanol and the obtained solution is charged into a column (manufactured by Mitsubishi Chemical) with 600 ml of panel of resin SP850. Most concentrated fractions were recovered while eluting with an aqueous-ethanol solution with 20% water content and then the final product was recovered by performing the process described in Example 2 without evaporating the solvent and avoiding the step comprising thiourea do.

Example 15 (Recovery of ivermectin obtained from reduction carried out on xenophase)

After the heterogeneous mixture was separated at the end of the reaction illustrated in Example 9, the obtained toluene solution was distilled off and the oil obtained was dissolved in 20 ml of a water-ethanol solution having a 12% fire content. The solution is filled into a column (manufactured by Mitsubishi Chemical) with 230 ml panel of resin SP850. Most concentrated fractions are recovered while eluting with an aqueous ethanol solution with a solvent mixture having the same composition and then concentrated to dryness. Then, according to the method described in Example 9, the final product is recovered by first crystallizing from a water-formamide-ethanol heterogeneous mixture and then from the water-ethanol heterogeneous mixture.

Claims (10)

Reaction between a dimer of rhodium chloride 1,5-cyclooctadiene and at least one phosphine having the formula (I) wherein the molar ratio between the dimer of rhodium chloride 1,5-cyclooctadiene and phosphine is 1: 3 and 1:12, preferably 1: 6), to prepare ivermectin, including reducing avermectin in the presence of a catalyst prepared in situ. Formula I [P (ArXn ₁ ) (ArXn ₂ ) (ArXn ₃ )] · nNa In the above formula, Ar is an aryl group, X is a sulfonic acid group SO ₃ , n ₁ , n ₂ and n ₃ are each independently 0 or 1, and n ₁ + n ₂ + n ₃ is equal to n, an integer of 0 or more. The method of claim 1 wherein the reduction is carried out in the presence of a solvent in both homogeneous and heterophasic phases. 3. The homogeneous phase according to claim 2, wherein n of the phosphine compound is at least one, and an alcoholic organic solvent or an aliphatic chlorinated solvent or an aliphatic esterified solvent selected from straight or branched C ₁ -C ₄ alkyl alcohols is used. (a) cooling the solution containing the reaction product and filtering to recover the catalyst; (b) recovering ivermectin from the solution obtained using known techniques; And optionally (c) recycling the recovered catalyst to its subsequent reduction process after appropriate recovery. The method of claim 2, wherein n of the phosphine compound is homogeneous and comprises using an aromatic, alcoholic, aliphatic chlorinated or aliphatic esterified organic solvent. A solvent according to claim 2, wherein n of the phosphine compound in heterogeneous phase is at least 1, and an aromatic, aliphatic chlorinated or aliphatic esterified organic solvent, preferably toluene, and a solvent incompatible with the organic solvent, preferably water. How to include. 6. The method of claim 5 wherein the organic phase first comprises a dimer of avermectin and rhodium chloride 1,5-cyclooctadiene and the incompatible phase comprises a phosphine and optionally a phase change material. The method according to claim 5 or 6, (α) separate phases; (β) ivermectin is recovered from the organic phase according to known techniques; Randomly (γ) A method comprising reusing a catalyst in a phase that is incompatible with the organic phase. The process according to any one of claims 1 to 3 and 5 to 7, wherein the phosphine is sodium diphenyl phosphinobenzene metasulfonate. The process according to claim 1, wherein the reduction is carried out at a temperature of 20 to 70 ° C., preferably 45 to 65 ° C., and a pressure of 4 to 8 atm, preferably 5 to 7 atm. 10. The recovery of ivermectin in the homogeneous or heterogeneous phase, according to any one of claims 1 to 9, wherein the obtained ivermectin solution is first concentrated and the resulting substrate is then absorbed with a styrene-divinyl benzene matrix. In an aqueous-alcoholic solvent mixture where water is 10-30% on a nonionic resin and the alcohol is a straight or branched C ₁ -C ₄ alkyl alcohol, wherein the resin / substrate ratio is 5 to 80 ml per gram of ivermectin. By eluting).