Organic compounds -- part of the class 532-570 series – Organic compounds – Carbohydrates or derivatives
Patent
1999-04-27
2000-06-06
Lee, Howard C.
Organic compounds -- part of the class 532-570 series
Organic compounds
Carbohydrates or derivatives
536 71, C07H 1708, C07H 1901
Patent
active
060720522
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a process for preparing ivermectin by selective hydrogenation of avermectin and subsequent removal of the catalyst.
Ivermectin is a known compound which has excellent biological activities and which is widely used as an anthelmintic, ectoparasiticide, insecticide and acaricide.
It is known (EP-A 0 001 689) to prepare ivermectin by selective catalytic hydrogenation from avermectin B.sub.1a and B.sub.1b. Avermectin is produced by biotechnological methods with the aid of Streptomyces avermitilis. It has five double bonds. To prepare ivermectin from this starting material, a selective catalyst is required which only hydrogenates the 22,23-double bond. ##STR1## Avermectin B.sub.1a (R: -ethyl) Avermectin B.sub.1b (R: -methyl)
From EP-A 0 001 680, it is known to use catalysts of the general formula [(R).sub.3 P].sub.3 RhX for this purpose, and Wilkinson's catalyst [Ph.sub.3 P].sub.3 RhCl is preferably employed. Relatively large amounts of this catalyst (0.05 to 0.5 mol/mol of avermectin) are employed here to achieve the desired hydrogenation.
After the hydrogenation, it is necessary to remove the noble metal as completely as possible from the product to obtain the active compound in a form which conforms to the specifications (heavy metal content<10 ppm).
For this reason, and because of the high cost of rhodium, it has been proposed (EP-A 0 059 616) to use a special recovery process for removing and recycling the considerable amounts of this noble metal which have to be used in the preparation of ivermectin.
This process, which is described in EP-A 59 616, comprises the treatment of the product solutions which are obtained after the hydrogenation with certain organic sulphur compounds at elevated temperatures, for example 95.degree. C., for several hours, followed by cooling the resulting mixture to from 0 to 5.degree. C. and then by filtration of the precipitated rhodium compounds and, if appropriate, extraction of the filtered organic crude solution with aqueous sodium carbonate solution for further purification.
The removal of the catalyst metal in this manner is both time- and energy-consuming, and in addition to this, the sensitive product is put under stress and the ligands (phosphines) which are contained in the catalyst remain in the product. In this procedure, the product is furthermore additionally contaminated by addition of an excess of organic sulphur compounds (5 mol/mol of rhodium). To prepare the pure active compound, these components have to be removed by recrystallization, which results in significant losses.
The present invention provides a process for preparing ivermectin which permits simple removal both of the rhodium employed and of the organic components of the catalyst system from the product solution which is obtained after the hydrogenation to give an active compound which can be processed with low loss of material to give a form suitable for use.
In this process, avermectin B.sub.1a and B.sub.1b is hydrogenated and both the catalyst metal and the organic components of the catalyst system are removed in a simple manner from the resulting reaction solutions.
In the process according to the invention, mixtures of avermectin B.sub.1a and B.sub.1b are reacted by selective hydrogenation using catalysts which are obtained in a manner known per se from rhodium salts or from complex rhodium compounds and phosphines, if appropriate by adding hydrazine or hydrazine salts, ##STR2## in which R, R' and R" independently of one another each represent hydrogen, alkyl or optionally alkyl-, alkoxy-, halogen- or halogenalkyl-substituted arylalkyl, or alkoxy- and/or optionally halogen- or halogenoalkyl-substituted divalent aromatic radicals, 1, least 12, the resulting reaction mixture, if appropriate after removal of the solvent, using lipophilic solvents.
The preparation processes for the catalysts are known (see, for example, Inorg. Synth. 10, 67 (1967) and EP-A 0 086 040, EP-A 0 283 615 and Tetrahedron Vol. 7, No. 19/20, p. 2087-2089 (1988)). The rhodium compounds sui
REFERENCES:
patent: 5656748 (1997-08-01), Arlt et al.
Arlt Dieter
Bonse Gerhard
Akorli Godfried R.
Bayer Aktiengesellschaft
Gil Joseph C.
Lee Howard C.
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