HK1024485B - Method for the production of ivermectin - Google Patents

Description

Process for preparing ivermectin

The invention relates to a method for producing ivermectin (ivermectin) by selective hydrogenation of avermectin followed by separation of the catalyst.

Ivermectin is a well-known compound with excellent biological activity and is widely used as anthelmintic, ectoparasiticide, insecticide and acaricide.

It is known (EP-A0001689) to synthesize avermectins from avermectins B_1aAnd B_1bThe ivermectin is prepared by selective catalytic hydrogenation. Avermectins, which have five double bonds, can be prepared biotechnologically with the aid of avermectins as streptomycins. In order to prepare ivermectin from this starting material, a selective catalyst is necessary which hydrogenates only the 22, 23-double bond.

Avermectin B_1a(R: -ethyl)

Avermectin B_1b(R: -methyl)

It is known from EP-A0001689 to use the general formula [ (R)₃P]₃RhX catalyst, preferably Wilkinson catalyst [ Ph ]₃P]₃RhCl. To achieve the desired hydrogenation, relatively large amounts of this catalyst (0.05 to 0.5mol/mol avermectin) can be used.

After the hydrogenation, the noble metals must be removed from the product as completely as possible in order to obtain active compounds in accordance with the specification (heavy metal content < 10 ppm).

For this reason and because rhodium is expensive, it has been proposed (EP-A0059616) to use special recovery methods to separate and recycle large amounts of this noble metal used in the preparation of ivermectin.

The process described in EP-A59616 comprises: the product solution obtained after hydrogenation with certain organic sulphur compounds is treated at elevated temperature (e.g. 95 ℃) for several hours, the resulting mixture is then cooled to 0-5 ℃, and the precipitated rhodium compounds are then filtered, if necessary, and the filtered crude solution is extracted with aqueous sodium carbonate solution for further purification.

In addition to the time and energy consumption for separating the catalyst metals in this way, the sensitive products are subjected to stress and the ligands (phosphines) contained in the catalyst remain in the product. In this step, the product is further contaminated due to the addition of an excess of organic sulfur compounds (5mol/mol rhodium). In order to prepare the pure active compounds, these components have to be isolated by recrystallization, which leads to a severe loss of product.

The invention provides a process for preparing ivermectin by easily separating rhodium used and the organic constituents of the catalyst system from the product solution obtained after hydrogenation, whereby active compounds are obtained which are usable with only a small loss of product during work-up.

In this method, avermectin B_1aAnd B_1bThe hydrogenation, catalyst metal and organic constituents of the catalyst system can be separated from the reaction solution obtained in an easy manner.

In the methods of the invention, avermectin B_1aAnd B_1bBy carrying out the selective hydrogenation reaction using catalysts which are obtained in a manner known per se from rhodium salts or complex rhodium compounds and phosphines, as phosphines, if appropriate, by using phosphines which form complexes of the formula (I), adding hydrazine or hydrazine salts,

wherein

R, R 'and R' independently of one another denote hydrogen, alkyl or optionally alkyl-, alkoxy-, halogen-or haloalkyl-substituted aralkyl,

A. a 'and A' independently of one another denote any alkyl-or alkoxy-and/or any halogen-or haloalkyl-substituted divalent aromatic radical,

m₁、m₂and m₃Identical or different and is 0 or 1,

the total number of carbon atoms in the alkyl and alkoxy groups is at least 12,

the ivermectin is obtained and the catalyst system is then separated from the resulting reaction mixture using a lipophilic solvent, if appropriate after separation of the solvent.

Methods for preparing catalysts are known (see, for example, Inorg. Synth.10, 67(1967) and EP-A0086040, EP-A0283615 and Tetrahedron Vol.7, No.19/20, P.2087-2089 (1988)). Rhodium compounds suitable as starting materials for the preparation of the catalysts are known; rhodium salts which may be mentioned as examples are rhodium (III) chloride hydrate and rhodium (III) bromide hydrate; suitable precursors from the series of rhodium complex compounds are, for example, (1c, 5 c-cyclooctadiene) rhodium (I) chloride dimer, 1, 5-hexadiene rhodium (I) chloride dimer and 2, 5-norbornadiene rhodium (I) chloride dimer, and (1, 5-cyclooctadiene) rhodium (I) acetylacetonate.

The phosphines of the formula (I) used according to the invention are known or can be prepared by known methods (cf. Houben-Weyl, Methoden der Organischen Chemie, 4th ed., vol.XII/1, Georg Thieme Verlag Stuttgart, 1963).

In the preferred phosphines of the formula (I) for use in the process of the present invention,

r, R 'and R' independently of one another denote hydrogen or C₁-C₂₀-alkyl or represents any C₁-C₂₀-alkyl-, C₁-C₂₀Alkoxy-, halogen- (especially chloro-, fluoro-, bromo-), 1, 5-halo-C₁-C₄Alkyl- (especially trifluoromethyl-) substituted aryl-C₁-C₄-alkyl (in particular benzyl or phenethyl),

A. a 'and A' independently of one another represent any C₁-C₂₀-alkyl-, C₁-C₂₀Alkoxy-, halogen- (in particular fluorine or chlorine-), 1, 5-halo-C₁-C₄An alkyl- (especially trifluoromethyl-) substituted divalent aromatic radical (especially phenyl), and

m₁and m₂Is 1 and m₃Is 0, the total number of carbon atoms in the alkyl and alkoxy radicals being at least 12, preferably at least 15, particularly preferably at least 18.

In particularly preferred phosphines of the formula (I),

r, R 'and R' independently of one another denote hydrogen or C₁-C₂₀-alkyl or represents any C₁-C₂₀-alkyl-, C₁-C₂₀Alkoxy-, halogen- (especially chloro-, fluoro-, bromo-), 1, 5-halo-C₁-C₄Alkyl- (especially trifluoromethyl-) substituted aryl-C₁-C₄-alkyl (in particular benzyl or phenethyl),

A. a 'and A' independently of one another represent any C₁-C₂₀-alkyl-, C₁-C₂₀Alkoxy-, halogen- (in particular fluorine or chlorine-), 1, 5-halo-C₁-C₄An alkyl- (in particular trifluoromethyl-) substituted divalent aromatic radical (in particular phenyl), and

m₁、m₂、m₃the method for preparing the compound of the formula 1,

the total number of carbon atoms in the alkyl or alkoxy groups is at least 12, preferably at least 15, particularly preferably at least 18.

Examples that may be mentioned include:

(2-dodecyl-phenyl) -diphenyl-phosphine, (3-dodecylphenyl) -diphenyl-phosphine, (4-dodecylphenyl) -diphenyl-phosphine, bis- (4-tert-butylphenyl) - (4-dodecyl) -phosphine, tris- (4-tert-butylphenyl) -phosphine, bis-o-tolyl- (4-dodecylphenyl) -phosphine, (4-octadecylphenyl) -diphenyl-phosphine, dodecyl-diphenyl-phosphine, bis- (dodecyl) -phenyl-phosphine, methyl-bis- (dodecylphenyl) -phosphine, (4-trifluoromethylphenyl) -bis- (dodecyl) -phenyl-phosphine, (4-octadecyl) -bis- (4-chlorophenyl) -phosphine, bis- (2-methoxyphenyl) - (4-dodecylphenyl) -phosphine, (4-dodecyloxyphenyl) -diphenyl-phosphine, dodecylbenzyl-diphenyl-phosphine, 4-biphenyl-bis- (dodecylphenyl) -phosphine, tris- (octylphenyl) -phosphine, tris- (hexylphenyl) -phosphine, tris- (nonylphenyl) -phosphine, tris- (decylphenyl) -phosphine, bis- (hexadecylphenyl) -phenyl-phosphine, bis- (octadecylphenyl) -phenyl-phosphine.

After preparation, the catalyst can be isolated and used in purified form for the hydrogenation reaction. However, it is also possible and particularly advantageous to synthesize the catalyst in situ and to use the solution thus obtained for the selective hydrogenation. It is advantageous to add an excess of the phosphine used as ligand to the hydrogenation feed.

For the preparation of the catalyst systems, rhodium salts are used in a molar ratio to the phosphine of the formula (I) of from 1: 1 to 1: 20, preferably from 1: 1 to 1: 15, particularly preferably from 1: 3 to 1: 15 (see in particular EP-A0086046). If appropriate, hydrazine or derivatives thereof may be added in a molar ratio of from 1: 1 to 1: 10, based on the rhodium salt.

The amount of additional phosphine of formula (I) added to the process of the invention is of the order of 0.01 to 0.06 per mole of substrate (see EP-A086046); however, by experiment, the optimum amount thereof can be easily determined.

The catalytic hydrogenation can be carried out in conventional solvents, for example alcohols, aromatics, ethers, ketones, esters or solvent mixtures, such as methanol/hydrocarbon or acetone/hydrocarbon mixtures.

The hydrogenation temperature is about 40 to 100 ℃ and the hydrogenation pressure is about 1 to 50 bar. In order to shorten the reaction time, the reaction is advantageously carried out under superatmospheric pressure, preferably at a pressure of from 3 to 20 bar.

Due to the lipophilic nature of the phosphines used as catalyst ligands according to the invention, the catalyst system can be separated from the product in a simple manner by extraction with a suitable lipophilic solvent in which the product produced (ivermectin) is only sparingly soluble or completely insoluble.

Thus the catalyst system (metal complex and phosphine) can be separated from the residual product/catalyst mixture after the hydrogenation reaction by removing the solvent by vacuum distillation followed by extraction with a lipophilic solvent. The resulting ivermectin is substantially free of catalyst metal and ligand phosphine; the product can be obtained with high purity by recrystallization which is known per se and can be used for removing small amounts of by-products. The product can also be further purified by chromatography after separation of the catalyst system without substantial losses.

By way of example, lipophilic solvents suitable for the selective separation of the catalyst system include, for example, aliphatic hydrocarbons-cyclohexane, methylcyclohexane, isooctane, petroleum ether, cleaning naphtha having larger hydrocarbon radicals, such as tert-octyl methyl ether.

A variant of the separation of the catalyst system after the hydrogenation is the addition of a selective lipophilic solvent to the product/catalyst solution obtained after the selective hydrogenation and the distillative separation of the polar solvent component present in the hydrogenation reaction feed. This can lead to the ivermectin precipitating out without mixing and being separated off from the solution containing the catalyst system by decanting or filtration.

A further variant of the separation of the catalyst system after the hydrogenation step comprises the subsequent preparation of a two-phase mixture which allows the ivermectin to be separated off from the catalyst system (catalyst complex and excess phosphine). To this end, if desired, the solvent used in the hydrogenation step can be isolated by distillation, preferably under reduced pressure, and replaced by a solvent mixture suitable for the isolation, in order to protect the product mixture.

Suitable solvent mixtures for this separation step include lipophilic components (as described above) and water-miscible polar solvents and water. Suitable polar components for such solvent mixtures include, for example, methanol, ethanol, acetone, butanone, acetonitrile, tetrahydrofuran, formamide, dimethylformamide and N-methylpyrrolidone. The water content in such solvent mixtures may vary, depending on the choice of ingredients, and is generally from 5 to 60%, preferably from 10 to 40%.

It was found in the present invention that ivermectin is mainly enriched in the polar component and the catalyst system is mainly enriched in the lipophilic component if such a two-phase system is mixed with the crude product of the hydrogenation step. In this embodiment, the catalyst system is separated from the product in a continuous countercurrent flow using an extraction column.

A further embodiment of the process of the invention consists in using a solvent or solvent mixture which is capable of dissolving the starting materials and the products and the catalyst system at elevated temperatures corresponding to the hydrogenation conditions, whereby the desired product (ivermectin) is subsequently precipitated after sufficient cooling, but in which the metal complex catalyst and the ligand phosphine are capable of being dissolved even at low temperatures. In this case, the product substantially free of catalyst can be separated from the solution residue by filtration; when the solution residue is worked up by distillation, the catalyst metal can be obtained in the distillation residue in a simple manner and can then be recycled.

Such solvents have amphiphilic properties, i.e. contain both lipophilic moieties and polar groups. Examples which may be mentioned include isooctanol, dodecanol, methyl tert-octyl ether, mixtures of tert-butanol and isooctanol and also tert-butyl methyl ether and isooctane.

It has been found, very surprisingly, that the catalyst or catalyst system used according to the invention allows both the hydrogenation of avermectins to ivermectin with good selectivity and the separation of the product and the catalyst system by simple means.

Examples

Example 1

A) Preparing a catalyst:

a mixture of 7.5mg of rhodium trichloride, 30.9mg of tris- (hexylphenyl) -phosphine, 3ml of acetone and 15. mu.l of hydrazine hydrate was heated under stirring in a hydrogen atmosphere and cooled under reflux for 4 hours.

B) Hydrogenation:

adding the catalyst solution obtained in (A) to 4.3g of avermectin (B)_1aAnd B_1bMixture) in 25ml of a 2: 1 solution of acetone/cyclohexane mixture. After addition of 51.4mg of tris- (hexylphenyl) -phosphine, the hydrogenation was carried out in a steel autoclave under 5bar of hydrogen pressure and 88 ℃. After 4 hours of hydrogenation, HPLC analysis showed that the starting material contained 8.9% and ivermectin (B)_1aAnd B_1bMixture) 89.9% and contains < 0.1% of tetrahydroavermectin.

C) Separation of catalyst system

After distilling off the solvent mixture, the crude product obtained in (B) was dissolved in a mixture of 35ml of methanol and 20ml of water, and the solution was extracted with 25ml of cyclohexane in a separatory funnel. The phases were separated and concentrated under reduced pressure. This extraction process was repeated twice in the same manner. As a result: the crude product from the hydrogenation step contained 690ppm Rh

The product obtained after the first extraction contained 39ppm Rh

After the second extraction 29ppm Rh

After the third extraction 22ppm Rh

The catalyst system (catalyst and phosphine) extracted from the product contained 6332ppm Rh.

Example 2

A) Preparing a catalyst:

a mixture of 7.5mg of rhodium trichloride, 45.6mg of tris- (octylphenyl) -phosphine (94% purity), 3ml of acetone and 15. mu.l of hydrazine hydrate was heated under stirring and cooled under reflux for 4 hours under an argon atmosphere.

B) Hydrogenation:

after addition of 53.2mg of tris- (octylphenyl) -phosphine, 4.3g of avermectin (B) were hydrogenated using the conditions given in example 1(B)_1aAnd B_1bA mixture). After 7 hours of hydrogenation, a crude ivermectin product containing 1.3% avermectin, 94.8% ivermectin and 2% tetrahydroavermectin was obtained according to HPLC analysis.

C) Separation of catalyst system

The product obtained was worked up by the method of example 1 (C). After three extractions, a product with a rhodium content of 9ppm was obtained.

Claims (2)

1. Process for the preparation of ivermectin B, characterized in that avermectin B is reacted by means of a catalyst_1aAnd B_1bIs obtained in a manner known per se from a rhodium salt or a complex rhodium compound and a phosphine as phosphine, which can be obtained by reacting a phosphine of formula (I) to form a complex, adding hydrazine or a hydrazine salt,

wherein

R, R 'and R' independently of one another denote hydrogen, alkyl or optionally alkyl-, alkoxy-, halogen-or haloalkyl-substituted aralkyl,

A. a 'and A' independently of one another denote any alkyl-or alkoxy-and/or any halogen-or haloalkyl-substituted divalent aromatic radical,

m₁、m₂and m₃Identical or different and is 0 or 1,

the total number of carbon atoms in the alkyl and alkoxy groups is at least 12,

to obtain ivermectin, and then separating the catalyst system from the reaction mixture obtained by means of a lipophilic solvent.

2. The process of claim 1, wherein the catalyst system is removed from the reaction mixture after the solvent is removed.