Classifications

• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H19/00—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof
  • C07H19/01—Compounds containing a hetero ring sharing one ring hetero atom with a saccharide radical; Nucleosides; Mononucleotides; Anhydro-derivatives thereof sharing oxygen
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H1/00—Processes for the preparation of sugar derivatives
• • C—CHEMISTRY; METALLURGY
  • C07—ORGANIC CHEMISTRY
  • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
  • C07H17/00—Compounds containing heterocyclic radicals directly attached to hetero atoms of saccharide radicals
  • C07H17/04—Heterocyclic radicals containing only oxygen as ring hetero atoms
  • C07H17/08—Hetero rings containing eight or more ring members, e.g. erythromycins

Definitions

• 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.
• 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.
• 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 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.
• thiourea from 2 to 12 mol/mol of Rh
• Rh which is known to be a reactive showing remarkable ecological and environmental drawbacks, are yet used in this treatment.
• 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 S0 3 , each of n-i, n 2 , and n 3 is independently equal to 0 or 1 and ni+ 2 +n 3 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.
• 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 C 1 -C 4 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
• an alcoholic organic solvent selected from linear or branched C 1 -C 4 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
• Ivermectin is finally isolated from the alcoholic solution by known techniques. For instance, the recovery of ivermectin can
• 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: ( ⁇ ) separing the phases;
• 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.
• the catalytic complex of the process of the invention 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.
• 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 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.
• 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.
• 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.
• 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%.
• 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.
• 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.
• Main signals (m/z) 874, 856, 730, 712, 586, 568, 550, 307, 293, 195, 145 and 113.
• 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.
• 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.
• Example 2 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.
• the yield of the reaction is comparable to the one obtained in the Example 2 (higher than 98%) .
• 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.
• Example 9 The procedure of the Example 9 was repeated in the absence of the quaternary ammonium salt; The yield of the reaction was 70%.
• 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.
• 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.

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• 1997
  • 1997-02-27 IT IT97MI000439A patent/IT1289993B1/it active IP Right Grant
  • 1997-08-04 JP JP10537199A patent/JP2000509729A/ja active Pending
  • 1997-08-04 EP EP97941910A patent/EP0915900A1/de not_active Withdrawn
  • 1997-08-04 KR KR1019980708579A patent/KR20000065035A/ko not_active Application Discontinuation
  • 1997-08-04 AU AU88427/98A patent/AU8842798A/en not_active Abandoned
  • 1997-08-04 WO PCT/EP1997/004227 patent/WO1998038201A1/en not_active Application Discontinuation
  • 1997-08-04 BR BR9708963-0A patent/BR9708963A/pt unknown

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