Method for debenzylation of dibenzylbiotin

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.

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 
a) adding a mineral acid to an aqueous solution of the dibenzylbiotin 
formed as intermediate, 
b) extracting undesired by-products and cleavage products with the aid of 
an organic solvent after a neutral to alkaline pH has been established, 
and 
c) crystallizing-out the liberated D-(+)-biotin by establishing an acidic 
pH and reducing the temperature, and separating the D-(+)-biotin off. 
In this process, it is advantageous according to the invention to use 
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. This can be carried 
out by adding a base from the group consisting of NaOH and KOH in the form 
of a dilute aqueous solution. After phase separation and further 
extraction of the organic phase with a basic solution, the pH of the 
aqueous phase is adjusted to about 5.5 to 6.0. This solution is 
subsequently treated with active carbon. The pH is then slowly reduced to 
1.3 with the aid of sulfuric acid at a temperature of about 80.degree. C., 
and the resultant solution is slowly lowered to a temperature of 5.degree. 
C., and the D-(+)-biotin is crystallized out. 
In this way, D-(+)-biotin is obtained in a purity of 99%, which corresponds 
approximately to food quality. The purity can be further increased by 
recrystallization. 
The examples below are given to further explain the novel process, but are 
not suitable for restricting the present invention to the parameters given 
in the examples.

EXAMPLES 
Comparative Example 
Preparation of biotin from dibenzylbiotin using hydrobromic acid: 
320 g of crude dibenzylbiotin (containing about 80% of pure dibenzylbiotin, 
0.6 mol) are mixed with 1200 g of 40% hydrobromic acid, and the mixture is 
refluxed for 48 hours. The benzyl bromide formed during this time (about 
200 g) is removed as the lower phase using a water separator. The excess 
hydrobromic acid is then distilled off. The residue is taken up in 1 l of 
water and 300 ml of xylene, and the solution is heated to about 90.degree. 
C. A pH of 9 is then established using sodium hydroxide solution, and the 
phases are separated. The aqueous phase is evaporated to half, and a pH of 
12 is established using sodium hydroxide solution. The apparatus is then 
evacuated. While the pH is kept constant at 12, 130 g of phosgene are 
slowly blown into the evacuated apparatus at 30.degree. C. When the 
reaction is complete, the vacuum is broken, and the pH is reduced to 7.0 
using nitric acid or sulfuric acid. 5 g of active carbon are added, the 
batch is subjected to a polishing filtration and heated to 80.degree. C., 
and the pH is slowly reduced to 1.5 using nitric acid (or sulfuric acid). 
After the mixture has been cooled overnight, the precipitated biotin is 
filtered off with suction and dried, giving 135 g of biotin (content: 
about 93%, corresponding to 125 g of pure biotin=0.51 mol, 85% of theory). 
Example 1 
Preparation of biotin from dibenzylbiotin using sulfuric acid: 
320 g of crude dibenzylbiotin (containing about 80% of pure dibenzylbiotin, 
0.60 mol) are mixed with 125 g of water, and 500 g of sulfuric acid are 
carefully added with stirring at such a rate that the temperature of the 
batch does not exceed 115.degree. C. Stirring is then continued at 
115.degree. C. for 3 hours. 2.5 l of xylene are added, and the mixture is 
then firstly neutralized using 5 l of 9% sodium hydroxide solution and 
then rendered alkaline. The aqueous phase is separated off. The xylene 
phase is extracted twice more with 0.5 1 of 9% sodium hydroxide solution 
in each case. The aqueous phase and the sodium hydroxide phases from the 
post-reactions are combined and adjusted to a pH of 6 at 80.degree. C. 
using sulfuric acid. 12 g of activated carbon are added, the mixture is 
subjected to a polishing filtration, and the pH is slowly reduced to 1.5 
using sulfuric acid. After the mixture has been cooled overnight, the 
precipitated biotin is filtered off with suction and dried, giving 128 g 
of biotin (content: about 99%, corresponding to 126 g of pure biotin=0.52 
mol, 86% of theory).