WO1998038201A1

WO1998038201A1 - Process for the preparation of ivermectin

Info

Publication number: WO1998038201A1
Application number: PCT/EP1997/004227
Authority: WO
Inventors: Loris Sogli; Enrico Siviero; Alessandro Rossi; Daniele Terrassan; Ermanno Bernasconi; Pilar Terreros; Francisco Salto
Original assignee: Antibioticos S.P.A.
Priority date: 1997-02-27
Filing date: 1997-08-04
Publication date: 1998-09-03
Also published as: JP2000509729A; EP0915900A1; ITMI970439A1; AU8842798A; BR9708963A; IT1289993B1; KR20000065035A

Abstract

There is disclosed a process for the preparation of ivermectin by reduction of avermectin which allows to obtain a final product having a high purity and in quite quantitative yields.

Description

PROCESS FOR THE PREPARATION OF IVERMECTIN

The invention relates to a process for the preparation of ivermectin by reduction from avermectin.

Ivermectin (22, 23-dihydroavermectin) shows parasiticide activity (as an anthelmintic, ecto- parasiticide, insecticide and acaricide) and is currently used either for the treatment of human beings or in veterinary or in agriculture.

The selective reduction of avermectin to ivermectin is known and is carried out in a homogeneous phase with the Wilkinson catalyst which is made of the complex between rhodium (I) chloride and three molecules of triphenylphosphine.

The reaction, disclosed in the patent US 4 199 569, allows the regio-specific hydrogenation of the 22,23 double bond which, among the five unsaturations present in the molecule, is the only cis di-substituted double bond, and sterically less hindered.

The treatment of the reaction product for the recovery of ivermectin following the known processes results quite troublesome. Indeed, it is necessary to first distillate the solvent, currently toluene, until an oily residual is obtained, which is recovered with solvents - to obtain a _^solution from which ivermectin is isolated by crystallisation by adding insolubilising agents, generally water. The first precipitation of ivermectin is carried out in a medium which contains the Wilkinson catalyst and the final product accordingly contains serious amounts of rhodium (100-200 ppm) as an impurity. The reaction product, in a variation of the process (disclosed in US 4413118) to enhance the recovery of rhodium and to reduce its content in ivermectin, is treated, under reflux in an organic solvent, with compounds having a carbon-sulphur double bond, particularly thiourea, to isolate a complex of rhodium which is then directed to the metal recovery and to the preparation of fresh Wilkinson catalyst. Great amounts of thiourea (from 2 to 12 mol/mol of Rh) , which is known to be a reactive showing remarkable ecological and environmental drawbacks, are yet used in this treatment.

It has been now found and it is a subject of the present invention a process for the preparation of ivermectin which comprises the reduction of avermectin in the presence of a catalyst prepared in si tu by a reaction between the dimer of rhodium chloride 1, 5-cyclooctadiene and at least one phosphine having the following formula: [P(ArXnι) (ArXn2) (ArXn3) ] .nNa wherein Ar is an aryl group, X is a sulphonic group S0₃, each of n-i, n₂, and n₃ is independently equal to 0 or 1 and ni+ ₂+n₃ is equal to n which is an integer, greater than or equal to 0, wherein the molar ratio between the dimer of rhodium chloride 1, 5-cyclooctadiene and said at least one phosphine is comprised between 1:3 and 1:12, preferably 1:6. Preferably, Ar is a phenyl group C₆H₅-. The process of the invention can be carried out by realising the reduction in the presence of a solvent both in a homogeneous and in a heterogeneous phase.

The process of the invention, in a homogeneous phase, comprises, where in the above phosphine formula n is greater than or equal to 1, the use of an alcoholic organic solvent, selected from linear or branched C₁-C₄ alkyl alcohols, such as, for instance, methanol, ethanol, isopropanol, particularly isopropanol, or of an aliphatic chlorinated solvent, such as, for instance, methylene chloride, or of an aliphatic esterified solvent, such as, for instance, ethyl acetate, .and

the following steps:

(a) recovering the catalyst from the solution containing the reaction product by cooling and

filtering;

(b) recovering ivermectin from the resulting

solution by known techniques; and, optionally,

(c) recycling the recovered catalyst after an

adequate restoration thereof in a subsequent

reduction.

Actually, the major part of the catalyst,

which, following the steps just described, is recovered by separation by filtration, precipitates

from the reaction product by cooling; the catalyst,

suitably restored, is optionally reused in a

subsequent reduction. Ivermectin is finally isolated from the alcoholic solution by known techniques. For instance, the recovery of ivermectin can

be carried out, following the disclosure of US 4199569 and US 4413118, treating under reflux the

resulting ivermectin solution in an organic

solvent, commonly toluene, with thiourea, yet in an amount of thiourea (from 2 to 12 mol/mol of Rh) , which is sensibly lower in comparison with the one disclosed in said patent.

When a phosphine of the above formula where n=0 is used the process of the invention comprises the use of an aromatic, alcoholic, aliphatic chlorinated or aliphatic esterified, organic solvent; toluene, isopropanol, methylene chloride or ethyl acetate are respectively preferred.

The process of the invention, in a heterogeneous phase, comprises the use of a sulphonated phosphine and of an aromatic, aliphatic chlorinated or aliphatic esterified, organic solvent, preferably toluene, and a solvent non miscible with said organic solvent, preferably water: initially the organic phase comprises the avermectin and the dimer of rhodium chloride 1,5- cyclooctadiene and the non miscible phase comprises the sulphonated phosphine and, optionally, a phase transfer which can be selected from the compounds currently used in the field, particularly the quaternary ammonium salts and the alkyl sulphonates; preferably the phase transfer is tetrabutylammonium bromide.

The process of the invention, in a heterogeneous phase, further comprises: (α) separing the phases;

(β) recovering ivermectin from the organic phase according to known techniques and, optionally,

(γ) recycling the catalyst in the phase non- miscible with the organic one.

For instance, the recovery of ivermectin in heterogeneous phase can be carried out, following the disclosure of US 4199569 and US 4413118, concentrating the resulting organic phase containing ivermectin and treating it with a mixture of formamide and water and then cooling, filtering and washing, thus isolating the final product.

The reduction, both in the homogeneous and heterogeneous phases, is carried out at a temperature comprised between 20°C and 70°C, preferably between 45°C and 65°C, and at a pressure comprised between 4 and 8 atm, preferably between 5 and 7 atm. The process of the invention allows to carry out a selective reduction of avermectin to ivermectin obtaining a high purity and in quite quantitative yields, sensibly lowering the resulting by-products and further using a rhodium amount even ten-fold lower than the one used in the known processes.

The . most preferred sulphonated phosphine according to the invention is sodium diphenyl phosphinobenzene etasulphonate.

When a sulphonated phospine is used, the catalytic complex of the process of the invention, replacing the Wilkinson one, belongs to a class of catalysts, well known in literature, used, above all, in oxo syntheses such as, for instance, the preparation of aldheydes starting from olefins.

Besides, these catalysts show the peculiarity of being water soluble and, accordingly, of being able to be used in the double phase reactions of the olefins. Their preparation and use are disclosed in J. Chatt et al . , J. Chem Soc . 1958, 276, 88; A.F. Borowsky et al . , Nouveau Journal de Chemie, 1977, vol. 2, n. 2, .p.137-144; F. Joo and M.T. Beck, Reac . Kin. and Cat . Letters, 1975, vol. 2, n. 3, 257-263; E. Kuntz, Chemtech . Sept. 1987.

The advantage coming from using these sulphonated catalytic systems resides in the easy separation and recycle of the catalyst; in fact, the reaction product can be removed without transforming or destroying the catalyst, a consideration having a remarkable relevance when expensive catalysts, such as the ones comprising rhodium, are used.

A further advantage obtainable by carrying out the process of the invention in a heterogeneous phase stands in the possibility of further lowering the impurities both in comparison with the process of the invention carried out in a homogeneous phase and with the process carried out with the (known) Wilkinson catalyst.

A still further subject of the present invention is provided by carrying out the recovering of ivermectin either in a homogeneous or heterogeneous phase first concentrating the resulting ivermectin solution, and then eluting the resulting concentrate in a aqueous-alcoholic solvent mixture, wherein the water in said mixture is 10-30% and the alcohol is a linear or branched C1-C4 alkyl alchol, on adsorbing non-ionic resins having a styrene-divinyl benzene matrix, wherein the resin/ivermectin ratio ranges 5 to 80 ml per gram of ivermectin.

The recovering of ivermectin, according to the invention, can be thus preferably carried out by eluting the substrate, resulting either from the reduction in homogeneous or heterogeneous phase, in in an aqueous-alcoholic solvent mixture, the most preferred alcohols being methanol, ethanol and isopropanol, on adsorbing non-ionic resins having a styrene-divinyl benzene matrix, f.i. of the HP and SP series produced by Mitsubishi Kasei: the resulting ivermectin elutes with the mobile phase whereas rhodium stays linked to the stationary phase. The recovering of ivermectin according to the preferred aspect of the invention just described allows to obtain the final product with quite high yields, amounting to 85-90%, and very high grade, showing a rather poor rhodium content. Such recovering further allows lowering of the peculiar impurities of the process.

Further, the recovering according to the latest aspect of the invention just described shows the advantage of avoiding the use of thiourea. The following examples illustrate the invention with a non limitative purpose.

EXAMPLE 1

Preparation of a sulphonated phosphine

A sulphonated phosphine was prepared adapting the method disclosed in J. Chem . Soc . 1958, 276, 88. 10 g of triphenyl phosphine were added carefully to 20 ml of fuming (30%) oleum in- an inert atmosphere.

The dissolution of the triphenylphosphine was noted after some minutes and the solution resulted of a yellow colour. The reactor was heated by a hot water bath at 60°C and left under stirring for 1 hour. This acid solution was first cooled, then poured, by a dropping funnel, in 200 ml of demineralised water under a nitrogen stream.

Such solution was neutralised with 30% NaOH. During this step the crystallisation of a heterogeneous solid was noted. The crystallisation was completed cooling to 0-5°C. Filtering was carried out to recover the product (sulphonated pho sphine in admixture with sodium sulphate) .

The solid was recrystallised from water to remove sodium sulphate. The isolated crystal was dried under vacuum (20 mm Hg; 35°C; 8 hours) . The yield of the resulting sulphonated phosphine was about 80%.

EXAMPLE 2

Reduction in a homogeneous phase 500 ml of isopropyl alcohol and a mixture comprising 20 g of avermectin (made of 92% of the B_ιa isomer and of 5% of the B_lb isomer) , 750 mg of

[RhCl(COD)]2 (C0D=1, 5-cyclooctadiene) , produced- by

Aldrich, code 22,795-1, and 3.37 g of the sulphonated phosphine prepared in Example 1 (molar ratio phosphine/ [RhCl (COD) ]₂ = 6:1) were charged in a Parr 4522 M autoclave having a 1 litre stainless steel reactor.

The autoclave was closed, three washings with nitrogen and two with hydrogen were carried out and a hydrogen pressure till 7 atm was then applied. The stirring was started and the temperature was gradually brought to 55°C.

After 7 h of reaction, the HPLC analysis revealed the disappearing of avermectin and its conversion into ivermectin (B_la and B_lb isomers) having a yield higher than 98% and the appearance of poor quantities of reaction by-products.

The reaction mixture was maintained to 0÷5°C, under slow stirring and nitrogen atmosphere for 12 hours. Filtering and washing was carried out with isopropanol; 2.45 g of a solid having a yellow- orange colour, mainly made of the species which catalyses the reaction, were recovered.

The resulting alcoholic solution was concentrated by distillation till an oil was obtained, which was dissolved in 750 ml of toluene. 0.96 g of thiourea were added maintaining under reflux for 8 hours. Cooling to 0÷5°C, maintaining to such temperature for about an hour and filtering were carried out. The solution was concentrated and the oil obtained was dissolved in 80 ml of ethanol; 200 ml of formamide and 40 ml of water were added to the solution at 45°C. Cooling and maintaining to room temperature for 12 hours were carried out. Filtering, washing with a 3:1 water-ethanol mixture and dissolving the isolated solid in 80 ml of ethanol, were carried out. 80 ml of water at 45°C, were added to the solution, cooling was carried out; maintaining to room temperature overnight, filtering and washing with a 1:1 water in ethanol mixture were carried out. 17 g of the finished product, characterised by the following analytical techniques, were isolated.

¹H-NMR (CDCI3, 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 I'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, OCH3) ; 3.44 ppm (s, OCH3) ; 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 ( , 2H-8a) ; 4.78

ppm (d, H-l') ; 4.98 ppm [d, H-15 (CH=) ] ; 5.34 ppm (m, H-19) ; 5.40 ppm (d, H-l") ; 5.43 ppm [s, H-

3(=CH-)1; 5.74 ppm [ , H-10 e H-ll (HC=CH-) ] ; 5.87

ppm [d, H-9(=CH-) ] .

¹³C-NMR (CDCI3, 300 MHz)

173.8 ppm, C(l); 139.6 ppm C(8) ; 138.0 ppm,

C(ll); 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(l") ; 97.5 ppm, C(21) ; 94.8 ppm, C(l') ; 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, OCH3, 56.4 ppm, OCH3; 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 (El, 90 eV of actual ionisation, 0.5 mA,

3kV of acceleration, starting T 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)

Signal having an absolute maximum at 244.7 nm.

Such data confirm those ones reported in literature for ivermectin: Analytical profiles of drug substances, 1988, Vol. 17, p. 155-184.

EXAMPLE 3

Reduction in a homogeneous phase

1.5 1 of isopropyl alcohol, 12 g of avermectin

(made of 93% of B_la isomer and of 4.5% of the B_lb isomer), 0.17 g of [RhCl (COD) ] ₂, produced by

Aldrich, and 0.53 g of triphenylphosphine (molar ratio phosphine/ [RhCl (COD) ] ₂ = 3:1) produced by

Basf, were charged in the autoclave already used in the trial described in Example 2 having a 2 1 stainless steel reactor. The autoclave was closed, conditioning under nitrogen, for three times, then under hydrogen, for two times, was carried out, subsequently bringing, under hydrogen pressure, till 7 atm. Stirring was started, bringing gradually the temperature till 50°C. After 7 hours of reaction the HPLC analysis revealed the disappearing of avermectin and its conversion into ivermectin (B_la and B_ib isomers) , with a yield of 98%, and the formation of poor quantities of reaction by-products was also noted. The product, isolated from the reaction mixture according to the technique described in the foregoing Example, was characterised recording the NMR, UV and mass spectra; the data obtained by the analysis of the sample overlap with those ones reported at the bottom of the foregoing Example and to those ones described in literature. EXAMPLE 4 Reduction in a homogeneous phase 1.5 1 of toluene, 16 g of avermectin (made of 92% of B_la isomer and of 5% of the B_lb isomer) , 75 g of [RhCl (COD)] ₂ produced by Aldrich and 240 mg of triphenylphosphine (molar ratio phosphine/ [RhCl (COD) ]₂ = 6:1) produced by Basf, were charged in the autoclave already used in the trial described in Example 3. The autoclave was closed and conditioning, first under nitrogen then under hydrogen, was carried out. The reaction mixture was maintained under brisk stirring for 7 hours at 65°C and under a hydrogen partial pressure of 7 atm. The reaction course was followed by HPLC analysis. The analysis demonstrated that the conversion yield to ivermectin was greater than 95% and that there was the appearance of lowered quantities of reaction by-products. The reaction product, isolated according to the technique described in Example 2, was characterised recording the NMR, UV and mass spectra. The data obtained overlap with those ones inserted after the Example 2 and are in accordance with those ones reported in literature.

Further, the reduction course demonstrated to result basically unchanged even when water was added to the reaction mixture. EXAMPLE 5 Reduction in a homogeneous phase

600 ml of isopropyl alcohol, 12 g of avermectin ( made of 93% of B_la isomer and of 4.5% of the B_lb isomer), 450 mg of [RhCl (COD) ]₂ and 2 g of the sulphonated phosphine (molar ratio phosphine/ [RhCl (COD) ] ₂ = 6:1) prepared by the method disclosed in the Example 1, were charged in the autoclave already used in the trial described in Example 2. The autoclave was closed, conditioning under nitrogen, then under hydrogen, was carried out, subsequently bringing, under hydrogen pressure, till 7 atm. Stirring was started and bringing gradually the temperature till 60°C. After 6 hours of reaction the HPLC analysis revealed the disappearing of avermectin and its conversion into ivermectin (B_la and B_lb isomers) having a quite quantitative yield. The formation of poor quantities of reaction by-products was also noted. The product, isolated from the reaction mixture according to the technique described in Example 2, was characterised recording the NMR, UV and mass spectra; the data obtained by the analysis of the sample overlap with those ones reported at the bottom of Example 2 and to those ones described in literature. EXAMPLE 6

Reduction in a homogeneous phase. The experimental procedure described in the Example 2 was followed charging 750 mg of [RhCl (COD) ] ₂ and 6.74 g of sulphonated phosphine (molar ratio phosphine/ [RhCl (COD) ] ₂ = 12:1) and obtaining the conversion of the avermectin in ivermectin with a 40% yield. EXAMPLE 7 Reduction in a homogeneous phase without phosphine. The experimental procedure described in the Example 2 was repeated charging only 750 mg- of [RhCl (COD)] ₂ without phosphine: the conversion of avermectin in ivermectin with a yield of about 50% was obtained. The HPLC analysis revealed the presence of high quantities (higher than 15%) of degradation products.

EXAMPLE 8

Reduction in a homogeneous phase recycling the catalyst

The catalyst recovered in the Example 2 was reused in a reduction reaction repeating the procedure described in the Example 2 and reintegrating the 35% of the catalytic species consumed by adding 0.26 g of [RhCl (COD) ]₂ and 1.18 g of phosphine obtained as described in the Example 1 (resulting molar ratio phosphine/ [RhCl (COD) ] ₂ = 3:1). The yield of the reaction is comparable to the one obtained in the Example 2 (higher than 98%) .

EXAMPLE 9

Reduction in a heterogeneous phase

A solution obtained dissolving 3.5 g of aver e ctin (made of 93% of the B_la isomer and of 4.5% of the B_ib isomer) and 130 mg of (98%) [RhCl (COD) ]₂ in 350 ml of toluene, was first charged, then a solution obtained by dissolving 0.59 g of -the sulphonated phosphine (phosphine/ [RhCl (COD) ] ₂ ratio

= 6:1), prepared according to the method described in the Example 1, and 515 mg of tetrabutylammonium bromide in 85 ml of water was charged in the autoclave already used for the trial described in the Example 2. The autoclave was closed, then a first washing with nitrogen and a second one with hydrogen were carried out. The, heterogeneous mixture was maintained under brisk stirring for 7 hours at 65°C and under a hydrogen pressure of 7 atm. The reaction course was followed by HPLC analysis. The analysis demonstrated that the yield of the conversion to ivermectin was higher than 98% and that there was the appearance of further lowered quantities of reaction by-products (equal to about a half of it) in comparison with the process of the invention in a homogeneous phase (see Example 2) ; besides, it is possible to observe such lowering even with respect to the process of the US 4 199 569, carried out using the Wilkinson catalyst.

The toluene solution, obtained after separating the heterogeneous mixture at the end of the reaction, was concentrated by distillation and the oil obtained was dissolved in 14 ml of ethanol. The resulting aqueous phase, containing the catalyst, was separated and can be optionally recycled in a subsequent reduction.

35 ml of formamide and 7 ml of water were added, at 45°C, to the ethanol solution of the oil. Cooling, maintaining at room temperature overnight, filtering and washing the solid thus obtained with a 25% solution of ethanol in water, were carried out. The raw product was dissolved in 13 ml of ethanol; 13 ml of water were added to the solution, at 45°C, cooling, maintaining at room temperature for 12 hours, filtering and washing with a 1:1 mixture of water in ethanol, were carried out. 3 g of the finished product, characterised by UV, NMR and mass, were isolated. The data obtained overlap with those ones reported at the bottom of the Example 2. EXAMPLE 10

Reduction in a heterogeneous phase A solution obtained dissolving 4 g of avermectin (made of 92% of the B_la isomer and of 5% of the Bib isomer) and 150 mg of [RhCl (COD) ]₂ in 600 ml of toluene, was first charged, then a solution obtained by dissolving 0.68 g of the sulphonated phosphine, prepared according to the method described in the Example 1, (phosphine/ [RhCl (COD) ]₂ ratio = 6:1), and 0.79 g of tetrabutylammonium bromide in 150 ml of water was charged in a Parr 4522 M autoclave having a 1 litre stainless steel reactor. The autoclave was closed and washing first with nitrogen then with hydrogen was carried out. The heterogeneous mixture was maintained under brisk stirring for 9 hours at 60°C and under a hydrogen pressure of 6 atm. The reaction course was followed by HPLC analysis. The analysis demonstrated that the yield of the reaction is quantitative and that there was the appearance of lowered quantities of reaction by-products. The reaction product, isolated according to the technique described in the foregoing Example, was characterised recording the NMR, UV and mass spectra. The data obtained overlap with those ones inserted after the Example 2 and are in accordance with those ones reported in literature. EXAMPLE 11

Reduction in a heterogeneous phase The experimental procedure described in Example 9 was followed charging 130 mg of [RhCl (COD)] ₂ and 0.3 g of sulphonated phosphine, equivalent to a [RhCl (COD) ] ₂/phosphine molar ratio from 1 to 3. The conversion of avermectin to ivermectin was obtained with a yield of 85%. The amount of the degraded product was negligible.

EXAMPLE 12

Reduction in a heterogeneous phase without phase tranfer

The procedure of the Example 9 was repeated in the absence of the quaternary ammonium salt; The yield of the reaction was 70%.

EXAMPLE 13

Reduction in a heterogeneous phase recycling the catalyst. A solution obtained dissolving 3.5 g of avermectin (made of 92% of the B_la isomer and of 5% of the Bi isomer) in 350 ml of toluene, was first charged, then the aqueous phase isolated at the end of the reaction described in the Example 9 was charged in the autoclave already used in the Example 2. The mixture obtained was reacted at 65°C for 7 hours and under a hydrogen pressure of 7 atm.

Some of the experimental data are reported in the following Table to illustrate the considerations drawn and with a comparative purpose in respect of the reduction with the (known) Wilkinson catalyst; the data which refer to the reduction carried out using the Wilkinson catalyst were drawn from the Example 11 of the US patent nr. 4 199 569.

TABLE

deduction with Wilkinson [RhCl(PAr)₃] (known)

EXAMPLE 14 (recovery of ivermectin resulting from the reduction carried out in a homogeneous phase)

The alcoholic solution resulting from the conversion of avermectin carried out in Example 3, was concentrated till an oil was obtained. The resulting oil was dissolved with 72 ml of 20% aqueous ethanol and the resulting solution was charged on a column having a 600 ml panel of the resin SP850 produced by Mitsubishi Kasei. The most concentrated fractions were collected eluting the aqueous-ethanolic solution having a 20% water content, then evaporating the solvent and recovering the final product following the procedure described in Example 2 yet avoiding the steps involving thiourea.

EXAMPLE 15 (recovery of ivermectin resulting from the reduction carried out in a heterogeneous phase)

The toluene solution, obtained after separing the heterogeneous mixture at the end of the reaction illustrated in Example 9, was concentrated by distillation and the oil obtained was dissolved in 20 ml of water-ethanol solution having a 12% water content. The solution was charged on a column having a 230 ml panel of the resin SP825 produced by Mitsubishi Kasei. The most concentrated fractions were collected eluting the aqueous ethanol solution with a solvent mixture having the same composition, then dried by concentrating. The final product was then recovered following the procedure described in Example 9 carrying out a first crystallisation from water-formamide-ethanol ternary mixtures and a second one from water- ethanol binary mixtures.

Claims

1. A process for the preparation of ivermectin which comprises the reduction of avermectin in the presence of a catalyst prepared in si tu by a reaction between the dimer of rhodium chloride 1,5- cyclooctadiene and at least one phosphine having the following formula:

[P(ArXn╬╣) (ArXn2) (ArXn3) ] .nNa wherein Ar is an aryl group, X is a sulphonic group S0₃, each of n_lf n₂, and n₃ is independently equal to 0 or 1 and n_!+n₂+n₃ is equal to n which is an integer, greater than or equal to 0, wherein the molar ratio between the dimer of rhodium chloride 1, 5-cyclooctadiene and the phosphine is comprised between 1:3 and 1:12, preferably 1:6.

2. A process according to claim 1, wherein the reduction is carried out in the presence of a solvent both in a homogeneous and in a heterogeneous phase.

3. A process according to claim 2, in the homogeneous phase, which comprises, where n is greater than or equal to 1, the use of an alcoholic organic solvent, selected from linear or branched C_!-C alkyl alcohols, or of an aliphatic chlorinated solvent or of an aliphatic esterified solvent, and the following steps:

(a) recovering the catalyst from the solution containing the reaction product by cooling and filtering;

(b) recovering ivermectin from the resulting solution by known techniques; and, optionally,

(c) recycling the recovered catalyst after an adequate restoration thereof in a subsequent reduc tion.

4. A process according to claim 2, in the homogeneous phase, which comprises, where n is equal to 0, the use of an aromatic, alcoholic, aliphatic chlorinated or aliphatic esterified, organic solvent.

5. A process according to claim 2, in the heterogeneous phase, wherein n is greater than or equal to 1 and which comprises the use of an aromatic, aliphatic chlorinated or aliphatic esterified, organic solvent, preferably toluene, and a solvent non miscible with said organic solvent, preferably water.

6. A process according to claim 5, wherein the organic phase comprises initially the avermectin and the dimer of rhodium chloride 1,5- cyclooctadiene and the non miscible phase comprises the phosphine and, optionally, a phase transfer. -

7. A .process according to any of claim 5 or 6, which comprises: (╬▒) separing the phases;

(╬▓) recovering ivermectin from the organic phase according to known techniques and, optionally,

(╬│) recycling the catalyst in the phase non- miscible with the organic one.

8. A process according to any of claims 1 to 3 and 5 to 7, wherein the phosphine is sodium diphenyl phosphinobenzene metasulphonate.

9. A process according to any one of the foregoing claims, wherein the reduction is carried out at a temperature comprised between 20┬░C and 70┬░C, preferably between 45┬░C and 65┬░C, and at a pressure comprised between 4 and 8 atm, preferably between 5 and 7 atm.

10. A process according to any one of the foregoing claims, wherein the recovering of ivermectin either in a homogeneous or heterogeneous phase is carried out first concentrating the resulting ivermectin solution and then eluting the resulting substrate in a aqueous-alcoholic solvent mixture, wherein the water in said mixture is 10- 30% and the alcohol is a linear or branched C╬╣-C₄ alkyl alcohol, on adsorbing non-ionic resins having a styrene-divinyl benzene matrix, wherein the resin/substrate ratio ranges 5 to 80 ml per gram of ivermectin.