WO1999058704A1

WO1999058704A1 - Method for producing mannite

Info

Publication number: WO1999058704A1
Application number: PCT/EP1999/002901
Authority: WO
Inventors: Thomas Mohr; Peter Johannes Mackert; Eugen Schwarz; Thomas Koppe
Original assignee: Merck Patent Gmbh
Priority date: 1998-05-11
Filing date: 1999-04-29
Publication date: 1999-11-18
Also published as: DE19820957A1; AU4136299A

Abstract

The invention relates to a multi-stage continuous method for producing mannite from invert sugar by a combination of catalytic hydrogenation and enzymatic isomerisation.

Description

Process for the production of mannitol

The invention relates to a multi-stage, continuously executable process for the production of mannitol starting from invert sugar by a combination of catalytic hydrogenation and enzymatic

Isomerization.

Processes for the preparation of mannitol are known from the literature, starting from pure fructose as the starting compound. The European patent application EP-A-0 006 313 describes the hydrogenation of _{ι n} fructose over a selective copper / SiO ₂ catalyst. Mannitol / sorbitol mixtures with a mannitol content of approx. 65% are obtained. The disadvantage of this method is that a relatively expensive raw material has to be used.

By hydrogenating invert sugar on a non-selective Raney nickel catalyst, mannitol / sorbitol mixtures with a mannitol content of

15 approx. 23-24% received (Ullmann's Enzyclopedia of Industrial Chemistry, Vol. A25, p. 424, VCH Verlagsgesellschaft, Weinheim, 1994). The yield of the target product mannitol is very low.

The combination of hydrogenation and enzymatic isomerization was developed by A.P.G. Kieboom and H. van Bekkum (Recl. Chim. Pays-

20 Bas 1984, 103, 1-12). Starting from invert sugar, hydrogenation is carried out in the presence of glucose isomerase immobilized on silica gel on a copper catalyst supported on silica gel. This takes advantage of the fact that fructose is hydrogenated significantly faster than glucose. The enzyme keeps the fructose / glucose ratio constant, while the fructose on the copper catalyst increases with approx. 65% selectivity

25 mannitol is hydrogenated. The disadvantage of the described method is that, on the one hand, it is necessary to work under relatively mild conditions, ie low temperatures, in order to prevent the temperature-sensitive enzyme from decomposing. The ideal reaction conditions for the enzyme are at 60-70 ° C, while the hydrogenation only proceeds at an appealing rate at 30 temperatures> 100 ° C. Furthermore, the enzyme must be protected against poisoning by dissolved copper by adding EDTA. Due to detached enzyme parts again the copper catalyst is slowly deactivated. The combination of enzymatic isomerization and catalytic hydrogenation in a one-pot process is therefore not suitable for a production process.

It is therefore an object of the present invention to provide an inexpensive, simple means for producing mannitol starting from an inexpensive raw material.

The present object is achieved by a process for the preparation of mannitol in which an invert sugar solution is catalytically hydrogenated and isomerized enzymatically in a multistage process. According to the invention, the hydrogenation takes place in the presence of a copper catalyst. It is carried out at a temperature of 80 to 120 ° C and a pressure of 120 to 200 bar.

Another feature of the process according to the invention is that it is carried out in the presence of 5 to 15% by weight of a copper catalyst, based on the amount of invert sugar contained in the reaction solution. The isomerization in the process is carried out in the presence of immobilized glucose isomerase at a temperature of 55 to 65 ° C.

This isomerization takes place after adding a small amount of magnesium sulfate as a cofactor and adjusting the pH to 7-7.5. The present invention furthermore relates to a corresponding process in which the hydrogenation step and the isomerization are carried out repeatedly until the residual sugar is completely hydrogenated. According to the invention, the invert sugar solution can be continuously circulated, partially hydrogenated on a copper catalyst, the glucose isomerized to fructose in the following step and part of the mannitol-containing reaction solution can be withdrawn continuously after the formation of mannitol, with new invert sugar solution being added to another in the same amount Place the system is fed back into the process. The present invention also relates in particular to a ~ ^-

corresponding process in which the hydrogenation is carried out on a fixed bed copper catalyst.

In a special embodiment of the process, the residual sugar of the reaction solution drawn off is hydrogenated in a separate fixed bed hydrogenation stage.

If invert sugar is used as the starting material, an inexpensive raw material that is available in large quantities is used for the production of mannitol. Through spatial separation of the enzymatic isomerization and the hydrogenation, each individual <. _Q reaction step carried out under the optimal conditions and thus a high reaction speed and a high throughput of the production plant are guaranteed. Mutual poisoning of the catalysts is also prevented and long service lives for the catalysts used can be achieved.

The hydrogenation of the glucose portion of the invert sugar leads to sorbitol,

15 while the fructose provides the appropriate proportions of mannitol and sorbitol depending on the selectivity of the catalyst used. When using an unselective catalyst, e.g. Raney nickel, the hydrogenation of invert sugar provides approximately 25% of mannitol. By using a selective copper-based hydrogenation catalyst, more than 25% mannitol can be obtained from the 20 fructose fraction of invert sugar: With a selectivity of 65%, about 33% mannitol is obtained from the fructose.

The process according to the invention can be carried out by hydrogenating a 40-70% invert sugar solution at a temperature of 80-120 ° C. at a pressure of 120 to 200 bar in the presence of a

05 selective catalyst. Copper catalysts have proven to be particularly selective in this reaction. These can have dopings of different transition metals or main group elements. In the suspension process, this catalyst is used in an amount of 5 to 15% by weight, based on the amount of sugar contained in the invert sugar solution. The glucose contained in the solution is characterized by

30 glucose isomerase, preferably immobilized isomerase, at one

Temperature isomerized from 55 to 65 ° C, especially at 60 ° C. It has proven to be particularly advantageous if before the isomerization a small amount of a magnesium (II) salt, for example magnesium sulfate, is added to the reaction mixture. It is also advantageous if the pH value is set to 7-7.5 before this reaction step.

The rate of hydrogenation of fructose when using a copper catalyst is significantly higher than that of glucose. This fact is used in the process described to increase the mannitol yield: if 50% invert sugar solutions with 10% catalyst content (based on invert sugar) are hydrogenated at 100 ° C and a hydrogen pressure of 150 bar up to a conversion of 50%, the hydrogenation solution contains approx. 10% fructose, 40% glucose in addition to 26% mannitol and 24% sorbitol.

The hydrogenation solution purified via ion exchanger is isomerized after addition of 50 ppm magnesium sulfate (Mg ²⁺ as cofactor) and adjustment of the pH to 7-7.5 using immobilized glucose isomerase (Sweetzyme T / Novo Nordisk) at approx. 60 ° C. Due to the equilibrium between glucose and fructose, the reaction solution contains about 25% fructose, 25% glucose, 26% mannitol and 24% sorbitol after the isomerization.

In a renewed hydrogenation step, the sugar / polyol mixture is hydrogenated with a selective catalyst under the conditions described above until conversion is complete. The hydrogenation solution contains approx. 42% mannitol and 58% sorbitol. The reaction solution can be worked up by the customary methods.

One of the advantages of the process described is that the combination of partial hydrogenation with an isomerization step can significantly increase the yield of mannitol compared to pure hydrogenation.

The separation of the isomerization and hydrogenation steps prevents the poisoning of the two catalyst systems, copper and glucose isomerase, which limits the service life of the catalysts in a one-pot process. - b -

NOT TO BE TAKEN INTO ACCOUNT FOR THE PURPOSE OF INTERNATIONAL PROCESSING

NO TENER EN CUENTA A LOS EFECTOS DE LA TRAMITACION INTERNACIONAL

NE PAS PRENDRE EN COMPTE AUX FINS DU TRAITEMENT INTERNATIONAL

6 -

Flow chart (<,>, = indicate the relative conditions)

Invert sugar mannitol + sorbitol

Hydrogenation hydrogenation

Fructose <glucose isomerization fructose = glucose

+ +

Mannitol> Sorbitol Mannitol> Sorbitol

The invention therefore relates to a multistage process for the preparation of mannitol starting from invert sugar by a combination of catalytic hydrogenation and enzymatic isomerization.

It has been found that the combination of the process steps can be carried out continuously in different orders and configurations.

Version 1 :

Step 1:

Hydrogenation of invert sugar with a selective copper catalyst up to a conversion of approx. 50%. The hydrogenation step can be carried out on powder as well as fixed bed catalysts. Invert sugar solution with a concentration of 40-70% can be used to carry out the process. Invert sugar solution with a concentration of 50% is preferably used.

Pressure range: 100-200 bar (preferably 160-180 bar) Temperature range: 80-160 ° C (preferably 100-120 ° C)

2nd step:

The hydrogenation solution is enzymatically isomerized using an immobilized glucose isomerase. A suitable enzyme can be used 7

commercially available isomerase can be used, e.g. B. Sweetzyme T / Novo Nordisk. After purification of the hydrogenation solution via ion exchanger to remove dissolved metal traces that can damage the enzyme, the pH is adjusted to 7.0-7.5 with the aid of dilute sodium hydroxide solution. After adding 50 ppm of magnesium sulfate as a cofactor, the solution thus prepared is passed over a fixed bed of immobilized glucose isomerase. This process step can be carried out analogously to the regulation given by Novo Nordisk.

Temperature: 60 ° C pH: 7.0-7.5

Cofactor: approx. 50 ppm Mg 2+

3rd step:

Complete hydrogenation of the residual sugar over a selective copper catalyst (preferably fixed bed catalyst); Reaction conditions analogous to the first hydrogenation step. Before the hydrogenation, the isomerization solution is freed from traces of enzyme which deactivate the hydrogenation catalyst over time. This can e.g. can be achieved with the help of common membrane filtration processes. The hydrogenation solution is purified and the two products sorbitol and mannitol are separated by the customary methods known to the person skilled in the art.

Depending on the selectivity of the hydrogenation catalyst, the following polyol components can be obtained from invert sugar using the process described:

Selectivity of the catalyst Mannitol fraction Sorbitol fraction with respect to mannitol [% 1 r% ι

60 39 61

65 41 59

70 46 54

75 49 51

80 52 49 8th -

Annotation:

The selectivity of the catalyst is variable and depends on both its structure and its doping. Copper / SiO ₂ (EP 6313) or Raney copper show a selectivity of 60-65%, copper / CPG (controlled pore glass), on the other hand, selectivities of 80-90% (M. Hegedüs, S. Göbölös, JL Margitfaivi in M. Guisnet et al. (Editors) Heterogeneous Catalysis and Fine Chemicals III, 1993, Elsevier Science Publishers, 187-194).

Variant 2:

Flow chart

Isomerization hydrogenation

Purification

The core plant consists of a hydrogenation and an isomerization section. The reaction solution is partially hydrogenated over a selective fixed bed catalyst. The fact that the selective copper catalyst fructose hydrogenates much faster than glucose is used here by experiments. The reaction solution becomes poor in fructose compared to glucose. This is subsequently supplied from glucose in the subsequent isomerization step. The isomerization solution is then passed through the hydrogenation stage again, and the newly formed fructose can again be selectively hydrogenated.

The invert sugar solution is fed into the circuit before the hydrogenation stage, and the same part of the reaction solution is again fed out after the isomerization stage. The turnover rate within the cycle is kept at 80-90%.

The residual sugar hydrogenation takes place in a subsequent separate fixed bed reactor hydrogenation stage over a selective copper catalyst.

On the one hand, the continuously alternating partial hydrogenation and isomerization advantageously provides the hydrogenated fructose from the reaction mixture continuously. Due to the spatial separation of the hydrogenation and isomerization stages, mutual poisoning of the two catalysts can be avoided and the optimal reaction conditions for the individual steps can be maintained.

In this way, the yield of mannitol can be increased significantly compared to the pure hydrogenation of invert sugar.

Depending on the selectivity of the hydrogenation catalyst, up to 60%

Yield of mannitol can be obtained. By optimizing the catalyst used and the set process conditions, these yields can be easily increased.

Claims

-10 PATENT CLAIMS

1. A process for the preparation of mannitol, characterized in that an invert sugar solution is catalytically hydrogenated and isomerized enzymatically in a multistage process.

2. The method according to claim 1, characterized in that the hydrogenation takes place in the presence of a copper catalyst.

3. The method according to the preceding claims that the hydrogenation is carried out at a temperature of 80 to 120 ° C and a pressure of 120 to 200 bar.

4. The method according to one or more of the preceding claims, characterized in that the hydrogenation is carried out in the presence of 5 to 15 wt .-% of a copper catalyst based on the amount of invert sugar contained in the reaction solution.

5 5. Method according to one or more of the preceding

Claims, characterized in that the isomerization is carried out in the presence of immobilized glucose isomerase at a temperature of 55 to 65 ° C.

6. The method according to one or more of the preceding 0 claims, characterized in that the isomerization after

Add a small amount of magnesium sulfate as a cofactor and adjust the pH to 7-7.5.

7. The method according to one or more of the preceding claims, characterized in that the hydrogenation step and 5 the isomerization is repeated until the complete hydrogenation of the

Residual sugar can be carried out.

8. The method according to one or more of the preceding claims, characterized in that a circulating invert sugar solution is partially hydrogenated on a copper catalyst Q, glucose isomerized to fructose in the following step, continuously after formation of the mannitol, part of the mannitol-containing reaction solution is subtracted and new ones in the same amount - 11 -

Invert sugar solution is fed back into the process at another point in the system.

9. The method according to one or more of the preceding claims 1-8, characterized in that the hydrogenation is carried out on a fixed bed copper catalyst.

10. The method according to claim 9, characterized in that the residual sugar of the withdrawn reaction solution is hydrogenated in a separate fixed bed hydrogenation stage.