Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Patent
1999-12-13
2000-10-31
Stockton, Laura L.
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
C07D49504
Patent
active
061405078
DESCRIPTION:
BRIEF SUMMARY
The present invention relates to a novel process for the selective debenzylation of dibenzylbiotin, which is formed as an intermediate in the synthesis of biotin, but is usually not isolated.
D-(+)-biotin is prepared in a multistep process, usually by Gerecke variants, as described by Gerecke, Zimmermann and Aschwanden in Helv. Chim. Acta 53 (1970) 991 ff. A common feature of all these methods is that at the end of the synthesis dibenzylbiotin (formula (I)) is formed, but is frequently not isolated. ##STR1##
The removal of the benzyl groups has hitherto only been possible in a complex multistep process. U.S. Pat. No. 4537973 discloses debenzylation reactions using methanesulfonic acids, but these can only be used on a bench scale. Corresponding reactions with sodium amalgam are no longer permissible for environmental protection reasons. This reaction is therefore carried out, in particular on a large industrial scale, virtually exclusively using hydrobromic acid, in exceptional cases also with hydroiodic acid. However, the latter cannot be carried out on a large industrial scale for cost reasons.
Although reactions with hydrobromic acid give yields of about 90% of theory, they have, however, severe disadvantages. These include, besides the high price of the hydrobromic acid, long reaction times of from 24 to 36 hours, during which the temperature must be kept at 145.degree. C., also the formation of lachrymatory benzyl bromide, which must either be purified for further dibenzylbiotin which can be carried out in a simile manner, at low temperatures and with a shortened reaction duration using inexpensive reagents, giving high yields of D-(+)-biotin of high purity.
The object is achieved by a process for the preparation of D-(+)-biotin by selective removal of benzyl groups by formed as intermediate, an organic solvent after a neutral to alkaline pH has been established, and pH and reducing the temperature, and separating the D-(+)-biotin off. impure dibenzylbiotin obtained, for example, as intermediate in the process described by DE-A1-4411101. The residue obtained after removal of the hydrogenation catalyst and removal of the solvent by distillation can be employed directly in the novel process described here.
The mineral acid used can be an acid from the group consisting of sulfuric acid and nitric acid, in particular sulfuric acid. The latter is used, in particular, as 70 to 80% sulfuric acid.
The novel process is characterized in that the mineral acid is added at a temperature of from 25 to 115.degree. C.
This process can be carried out by, after the reaction is complete, extracting undesired by-products and cleavage products with the aid of a suitable organic solvent from group consisting of toluene and xylene after a neutral to alkaline pH has been established, and, when the solvent extraction is complete, adjusting the pH to weakly acidic, in particular to a pH of 6, and treating the aqueous D-(+)-biotin-containing solution with active carbon. The D-(+)-biotin liberated can subsequently be crystallized out after the novel process after adjustment of the pH to a value of 1-2 by cooling the reaction solution, and then separated off.
It has been found by experiments that debenzylation of dibenzylbiotin can be carried out using inexpensive 70 to 80% sulfuric acid instead of expensive hydrobromic acid. Surprisingly, the removal of the benzyl groups proceeds without attack on the carbonyl groups. This advantageously allows omission of the phosgenation step after the debenzylation. In a fairly short reaction time of only 2 to 4 hours, the reaction proceeds at a temperature of from 105 to 125.degree. C. Lachrymatory substances are not formed, since no bromination of the departing benzyl groups can take place.
Furthermore, work-up of the D-(+)-biotin is much simpler than after debenzylation using hydrogen bromide:
After the debenzylation, a suitable organic solvent, such as, for example, xylene or toluene, is added to the reaction mixture. The pH of the solution is adjusted to between neutral and alkaline. Thi
REFERENCES:
patent: 4537973 (1985-08-01), Takahashi et al.
Bollinger Heinrich
Heywang Ulrich
Muller Hans-Rudolf
Merck Patent Gesellschaft mit
Stockton Laura L.
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