HK1022695B - Method for debenzylation of dibenzylbiotin - Google Patents

Description

The present invention relates to a new method for the more selective debenzylation of dibensylbiotin, which is formed as an intermediate in biotin synthesis but is not usually isolated.

D- ((+) -biotin is produced by a multi-stage process, mostly using variants of gerecke, as described by Gerecke, Zimmermann and Aschwanden in Heiv Chim. Acta 53 (1970) 991 ff. All these methods have in common that the end product of the synthesis is dibenzylbiotin (formula (I), which is often not isolated. Other

The removal of the benzyl groups is so far only possible in a complex process involving several steps. US-A-4537973 shows that debensylation reactions using methane sulphonic acid are known, but that they can only be used on a laboratory scale.

EP-A-0564723 describes the debenzylation of dibenylbiotin with hydrobromic acid.

Although theoretically, the yields of hydrobromic acid are about 90%, they have serious disadvantages, including the high price of hydrobromic acid, long reaction times of 24 to 36 hours, when the temperature must be maintained at 145 °C, the formation of unclean, tear-producing benzyl bromide, which can be either used for further processing or used for the production of other products.

The biotin molecule is decarbonised as a by-product, losing about 50% of the reaction product and being reintroduced into the molecule by a further step in a phosgene conversion process: Other

Following these steps, the 85% purity of the dibenzyl biotin obtained is approximately 93% purity biotin at a yield of 90% of the theory.

The present invention is therefore intended to provide a simple, low temperature, shorter reaction time process for the debenzylation of dibenzylbiotin (formula (I) using inexpensive reagents and yielding high purity D-(+) biotin at high yields.

The solution to the problem is a method to produce D- (((+) biotin by selective cleavage of benzyl groups by (a) an aqueous solution of the dibenzyl biotin formed as an intermediate is added to sulphuric acid, (b) undesirable by-products and fission products are extracted by means of an organic solvent after adjustment of a neutral to alkaline pH, and (c) the released D- (((+) biotin is crystallized and separated by adjustment of an acid pH and lowering of the temperature.

The method can be advantageously used in the present invention of unpurified dibenyl biotin, which is obtained, for example, as an intermediate in the process described by DE-A1-4411101. The use of sulphuric acid is particularly marked by its 70-80% content. The method of the invention is characterized by the addition of sulphuric acid at a temperature of 25 to 115 °C. This process can be carried out by extracting undesirable by-products and fission products after the reaction has been completed, after setting the pH to neutral to alkaline with the help of a suitable organic solvent from the toluene, xylol and group, and after solvent extraction, by adjusting the pH to a slightly acidic, in particular to a pH of 6, and by treating the aqueous D+ biotin-containing solution with activated carbon. The released D+ biotin can then be crystallized and separated by cooling the reaction solution to a pH between 1 and 2, according to the method of the invention.

Experiments have shown that a debenzylation of dibenylbiotin can be carried out by using cheap 70 to 80% sulphuric acid instead of expensive hydrobromic acid. Surprisingly, the cleavage of the benzyl groups occurs without the carbonyl groups being attacked. This way, the process step of phosgeneization following debenzylation can be avoided. In a short reaction time of only 2 to 4 hours, the translation occurs at a temperature of 105 to 125°C. Tear-inducing substances do not fall because no bromination of the leaving benzyl groups can be carried out.

Furthermore, the processing of D- ((+) biotin is much easier than after debenzylation with hydrogen bromide:

After debenzylation, a suitable organic solvent such as xylol, toluene or toluene is added to the reaction mixture. The pH of the solution is adjusted from neutral to alkaline. This can be done by adding a base from the NaOH group, KOH in the form of a diluted 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 then treated with activated carbon. Then, at a temperature of about 80 °C, the pH is slowly lowered to 1.3 by sulfuric acid and the resulting solution is slowly lowered to 5 °C, which decristallises D-biotin and bi-dioxide.

This gives D-(+) biotin a purity of 99% of theoretical, which is close to food grade.

The following examples are given to illustrate the process of the invention.

Examples Comparison example Manufacture of biotin from dibenylyl biotin with hydrobromic acid:

The remaining residue is taken with 1 I of water and 300 ml of xylol and heated to 135 °C and 90 °C. Then, with sodium bicarbonate, the phases are separated and set to a pH of 9 and the aqueous phase is reduced to half dry and replaced by a pH of 12 by a sodium bicarbonate. The excess hydrochloric acid is then distilled at a constant pH of 80 °C. The pH of the liquid is maintained at a constant pH of 80 °C. The residual pH is maintained at a constant pH of 80 °C. The sodium bicarbonate is then cooled to a pH of 9 and the phases are separated. The aqueous phase is then reduced to half dry and replaced by a pH of 12 by a sodium bicarbonate. The pH of the liquid is maintained at a constant pH of 0.51 °C. The residual pH is maintained at a constant pH of 80 °C. The sodium bicarbonate is then cooled at a constant pH of 5 or 130 °C. The residual pH of the active substance is maintained at a constant pH of 0.51 °C. The sodium bicarbonate is then cooled at a constant pH of about 130 °C. The residual pH of the active substance is maintained at a constant pH of 0.51 °C.

Example 1 Manufacture of biotin from dibenylbiotin with sulphuric acid:

320 g of raw dibenyl biotin (containing about 80% pure dibenyl biotin 0.6 mol) is added to 125 g of water and stirred gently with 500 g of sulphuric acid so that the temperature of the solution does not exceed 115 °C. After stirring for 3 hours at 115 °C, 2.5 I xylol is added, first neutralized with 5 I 9 % sodium biotin and then made alkaline. The aqueous phase is separated. The xylol phase is extracted twice with 0.5 I 9 % sodium biotin each. The water phase and the sodium biotin P-residues are combined and at 80 °C with sulphuric acid a pH of 6 is added. The additive is then filtered with 12 g of white coal. The dry phase is filtered overnight with a pH of 0.52%.

Claims (7)

1. Process for the preparation of D-(+)-biotin by selective removal of benzyl groups by

   a) adding water to the dibenzylbiotin formed as intermediate and adding sulfuric acid at temperatures of between 25 and 115°C.

   b) extracting undesired by-products and cleavage products with the aid of an organic solvent after an 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.
2. Process according to Claim 1, characterized in that impure dibenzylbiotin is used.
3. Process according to one or more of Claims 1 to 2, characterized in that 70 to 80% sulfuric acid is used.
4. Process according to one or more of Claims 1 to 3, characterized in that, when the reaction is complete, undesired by-products and cleavage products are extracted with the aid of an organic solvent from the group consisting of toluene and xylene after an alkaline pH has been established.
5. Process according to one or more of Claims 1 to 4, characterized in that, when the solvent extraction is complete, the pH is adjusted to weakly acidic, and the aqueous D-(+)-biotin-containing solution is treated with active carbon.
6. Process according to Claim 5, characterized in that the pH is adjusted to 6.
7. Process according to one or more of Claims 1 to 6, characterized in that the D-(+)-biotin is crystallized out by cooling the reaction solution after the pH has been adjusted to a value of 1 - 2 and is separated off.