Organic compounds -- part of the class 532-570 series – Organic compounds – Tetracyclo naphthacene configured ring system having at...
Patent
1989-05-05
1990-10-02
Raymond, Richard L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Tetracyclo naphthacene configured ring system having at...
502215, C07C23726
Patent
active
049609130
DESCRIPTION:
BRIEF SUMMARY
SPECIFICATION INVENTION
The present invention relates to an improved process for the preparation of doxycycline and methacycline and acid addition salts thereof by catalytic dehalogenation and hydrogenation by using a tellurium and/or selenium containing alloy catalyst, the latter being prepared according to this invention as well.
The following abbreviations are used throughout the specification: 4-dimethylamino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12,12a-pentahydroxy- 6-methylene-1,11-dioxo-2-naphthacene-carboxamide of the formula ##STR4## "chloro-methacycline": 4-dimethylamino-1,4,4a,5,5a,6,11,12-12a-nonahydro-3,5,10,12a-tetrahydroxy- 11a-chloro-6-methylene-1,11,12-trioxo-2-naphthacene-carboxamide of the formula ##STR5## "doxycycline": .alpha.-6-desoxy-5-hydroxy-tetracycline, i.e. 4-dimethylamino-1,4,4a,5,5a,6,11,12a-octahydro-3,5,10,12-12a-pentahydroxy- 6.alpha.-methyl-1,11-dioxo-2-naphthacene-carboxamide of the formula ##STR6## ".beta.-doxycycline" is the .beta.-isomer of doxycycline R stands for --CH.sub.3 or .dbd.CH.sub.2
BACKGROUND OF THE INVENTION
It is known that methacycline and doxycycline are very effective representatives of tetracycline type antibiotics.
Several processes are known for the preparation thereof using oxytetracycline as starting material and preparing chloromethacycline followed by dehalogenation and if desired by hydrogenation the obtained methacycline to doxycycline.
Dehalogenation was accomplished--among other methods--by introducing hydrogen gas in the presence of a catalyst, see e.g. Example 9 of Hungarian Patent No. 150909, wherein rhodium precipitated on active carbon was used.
This process, however, was not satisfactory as reaction products were produced which were difficult to separate from by-products and the conversion was not complete either. Therefore the use of secondary or tertiary phosphines has been recommended in Hungarian Patent No. 169 605. This process was accompanied with the disadvantage that an equimolar amount of tertiary or secondary phosphines was needed, resulting in a great amount of poisonous waste, and the formed phosphine oxide could be converted again to phosphine only by a multi-step reaction.
The introduction of hydrogen gas in the presence of a catalyst was also used for the saturation of the double bond of the methylene group at the 6-position on methacycline in order to produce doxycycline.
In the course of hydrogenation 6-desoxy-5-hydroxy-tetracycline of the formula (IV) can occur in the form of .alpha.- and .beta.-isomers. Only the .alpha.-isomer is valuable as medicine, i.e. doxycycline. The amount of the .alpha.-isomers during hydrogenation determines if the hydrogenation process is successful, i.e. if hydrogenation can be carried out selectively, to produce mainly .alpha.-isomer with a good yield and pure quality.
It is also known that 6-desoxy-5-hydroxy-tetracycline can be prepared with a yield of 60% by using a 5% palladium or rhodium catalyst on a carrier, but the product was a 1:1 mixture of .alpha.- and .beta.-isomers, which was followed by the separation of the .alpha.-isomer accompanied by further losses (U.S. Pat. No. 3,200,149). The ratio of the formation of the .alpha.-isomer can considerably be improved, if the noble metal catalyst on a carrier is poisoned by carbon monoxide, quinoline sulphur or other sulphur compounds. Thus the yield of the .alpha.-isomer could be increased to 40-50%, but even so the product had to be further purified due to the remaining 10% .beta.-isomer impurities (Hungarian Patent No. 156 925). In order to improve the stereoselectivity of hydrogenation an alloy catalyst consisting of the metals of platinum group, copper, silver or gold has been used and a doxycycline yield of about 70% has been disclosed with 1 to 10% .beta.-isomer impurities (Hungarian Patent No. 167 250).
A 92% .alpha.-isomer content has been achieved by using a catalyst containing palladium atoms located on ultra-microporous active carbon, without poisoning, with a yield of 76% (Hungarian Patent No. 169 667).
Hydrogenation coul
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Besenyei Gabor
Gyory Peter
Jelinek Istvan
Kallay Tamas U.
Lugosi Gyorgy
Chinoin Gyogyszer- es Vegyeszeti Termekek Gyara RT.
Covington Raymond
Dubno Herbert
Myers Jonathan
Raymond Richard L.
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