KR20020042176A - Method for preparing DL-α-tocopherol with a high yield and high purity - Google Patents

Abstract

PURPOSE: A process for preparing high purity DL-alpha-tocopherol is provided, therefore the subject compound can be cheaply prepared because Bronsted acid is not used and the amount of solid silica gel and/or silica-alumina used is significantly decreased. CONSTITUTION: The process for preparing high purity DL-alpha-tocopherol comprises the steps of: slowly adding isophytol or phytol derivatives into trimethylhydroquinone(TMHQ) in the presence of a reaction solvent using MX2 as a main catalyst and silica gel and/or silica-alumina as a cocatalyst at 0.5 to 3.0 KG and 100 to 170 deg. C for 2 to 10 hours and reacting them; and recovering the unreacted silica gel and/or silica-alumina by washing it with a polar solvent, wherein the reaction solvent is selected from aliphatic saturated carbohydrate, aromatic carbohydrate and polar solvent; the aromatic carbohydrate is toluene, benzene or xylene; the aliphatic saturated carbohydrate is n-heptane, mixed-heptane, n-hexane, mixed-hexane, n-octane, mixed-octane, n-decane or mixed-decane; the polar solvent is butylacetate, dichloroethane, dichloromethane, ethylacetate or diethylmalonate; the polar solvent is selected from methylacetate, ethylacetate, propylacetate, butylacetate, pentylacetate, acetone, methylethylketone, diethylketone, methylisopropylketone, methanol, ethanol, propanol, isopropylalcohol, butanol, pentanol, hexanol, heptanol and octanol.

Description

Method for preparing DL-α-tocopherol with a high yield and high purity}

The present invention relates to a method for producing DL-α-tocopherol in high yield and high purity through a condensation reaction of isopytol or phytol derivatives with trimethylhydroquinone (hereinafter referred to as "TMHQ"). More specifically, the present invention relates to Bronsted acid by condensation reaction of isopyitol or phytol derivatives with TMHQ in the presence of MX ₂ and a silica gel (or silica alumina) composite catalyst and in the presence of a high temperature and high pressure and an appropriate reaction solvent. Not only does not use but also relates to a method for producing DL-α-tocopherol that can significantly increase the economics of the process by significantly reducing the amount of solid silica gel used.

In recent decades, many attempts have been made to efficiently prepare DL-α-tocopherol using Zn (II) cationic compounds as metal catalysts (Lewis acid catalysts). In general, DL-α-tocopherol is prepared through a condensation reaction of isopyitol and trimethylhydroquinone as in Scheme 1 below.

As a prior art associated with the process, Nisshin US Pat. No. 4,217,285 yields yields in toluene or n-hexane solvents using ZnCl ₂ and silica-alumina (or silica-gel) in the presence of acids, especially hydrochloric acid. It is disclosed that DL-α-tocopherol of 99% or more and 95 to 96% purity can be synthesized.

In addition, US Pat. Nos. 4,634,781 and 4,639,533 to BASF disclose that isopytol is first reacted with or simultaneously injected with amines such as tridecylamine or octadecylamine, followed by TMHQ in the presence of ZnCl ₂ and hydrogen chloride. And a rather complex and inefficient process for the production of DL-α-tocopherols is disclosed. In particular, the patent reports that the yield of DL-α-tocopherol obtained is about 95-98%, and the purity is 94-95%.

As another method for preparing DL-α-tocopherols, US Patent Nos. 5,663,376 and 5,886,197, to Eisai, use ZnCl ₂ and HCl as catalysts to prepare apolar solvents with alcohols or carbonate esters. It is disclosed that DL-α-tocopherol can be prepared by reacting isopytol and TMHQ in a complex solvent system, where the yield is 94 to 98% and the purity is about 92 to 97%.

However, the DL-α-tocopherol prepared by the method of the above patents is relatively low in overall purity of 95%, and when the high purity DL-α-tocopherol is required, an additional purification process is required, thereby lowering economic efficiency. . In particular, in the case of BASF's patent or Aiza's patent, the yield of DL-α-tocopherol is not very satisfactory. In other words, when Bronsted acid, such as hydrochloric acid, used as a promoter exists from the beginning of the reaction, the amount of isopyitol dehydrated by Bronsted acid proceeds to self-decompose, resulting in a decrease in overall yield. Because.

In the case of using toluene or hexane as the reaction solvent, as in Nisin's patent, the overall yield is relatively low because, when using toluene, isopyitol reacts with some of the toluene to produce unwanted side reactions. In this case, the isopyitol does not react with the hexane, but because the boiling time (about 69 ℃) of the hexane is low because the reaction time is long, it is considered that the dehydration reaction of the isopyitol by the catalyst increases. In addition, when the reaction is performed using the solvent, a relatively large amount of side reactants having a similar structure to DL-α-tocopherol is present around the GC (gas chromatography) peak of DL-α-tocopherol. -It is difficult to separate at the time of final separation of tocopherol, so that there is a disadvantage that the purity is lowered or the yield is reduced when purified to high purity.

In addition, Nisin's patent uses silica gel or silica-alumina as a solid catalyst, and the yield is higher than in the case described above. However, since silica has adsorption to a specific organic material, TMHQ and reaction intermediates (condensation) in the reaction material are condensed. The reaction is rapidly degraded by the presence of two intermediates on the reaction mechanism) and the product, DL-α-tocopherol, adsorbed on the surface of the silica gel to intercept the active group of the silica gel catalyst. Therefore, the reuse of the silica gel catalyst becomes impossible. In addition, the overall reaction yield may also be reduced when the DL-α-tocopherol adsorbed on the surface of the silica gel is not recovered. In particular, in the Nisin patent, hydrochloric acid is present from the beginning, as mentioned above, hydrochloric acid decomposes isopitol to reduce yields, as well as causing other side reactions that may occur during condensation reaction between isopytol and TMHQ. Purity is lowered by generating by-products having a molecular weight similar to that of Vitamin E.

In order to solve the above problem, Korean Patent Application No. 99-57483 discloses 30 to 60 isopyitol or phytol derivatives at 80 to 135 ° C. using MX ₂ as a main catalyst and silica gel and / or silica alumina as a cocatalyst. Slowly add for minutes to form an intermediate, and then react with Bronsted acid in the reaction mixture to separate the final product, washing and recovering the remaining silica gel and / or silica-alumina with a polar solvent to obtain high yield. And a method for producing high purity DL-α-tocopherol. However, in the case of the present invention, since the operation at normal pressure, the amount of solid silica gel and / or silica-alumina is not only very large (50 to 150 parts by weight with respect to 100 parts by weight of TMHQ) but still using Bronsted acid (especially hydrochloric acid). Therefore, in terms of economics of the process is not so desirable.

On the other hand, the present inventors increase the reaction pressure to increase the reflux temperature of the solvent to increase the reaction rate, thereby maintaining the same dehydration reaction of isopyitol or phytol derivatives even at high temperatures and without using Bronsted acid. _{Using only 2} and silica gel (and / or silica-alumina) as a catalyst to develop a reaction to produce DL-α-tocopherol. In particular, the reaction can minimize the self-decomposition and by-product generation of isopyitol or phytol derivatives, it is possible to significantly reduce the amount of silica gel (and / or silica-alumina) used as a catalyst.

It is therefore an object of the present invention to provide a process for preparing DL-α-tocopherol in high yield and high purity.

Another object of the present invention is to provide a process for preparing DL-α-tocopherol in high yield and high purity without using Bronsted acid as a catalyst.

Still another object of the present invention is to provide a method for preparing DL-α-tocopherol, which can improve the economics of a process by reducing the amount of silica gel (and / or silica-alumina) used as a catalyst.

Another object of the present invention is to provide a method for producing a larger amount of DL-α-tocopherol in the same reactor by minimizing the amount of solvent used.

A method of preparing DL-α-tocopherol with high purity without using the Bronsted acid of the present invention for achieving the above object is carried out using a mixed catalyst system consisting of MX ₂ and a cocatalyst of a _divalent metal halogen compound. In the method for preparing DL-α-tocopherol through the condensation reaction of isopyitol and TMHQ, which is a reactant, an isopyitol or a phytol derivative is obtained by using a mixed catalyst system comprising MX ₂ and a cocatalyst. In the method for preparing DL-α-tocopherol through the condensation reaction of TMHQ, MX ₂ (wherein M is Zn, Fe or Sn, and X is F, Cl, Br or I) as a main catalyst in the presence of a reaction solvent ) And isopropyl is slowly added at 0.5 to 3.0 KG at 100 to 170 ° C. for 2 to 10 hours using silica gel and / or silica-alumina as a cocatalyst to obtain a reaction product, and the remaining cocatalyst silica is silica. It is characterized in that the gel and / or silica-alumina is recovered by washing with a polar solvent.

1 is a process diagram schematically showing one embodiment of a process for producing DL-α-tocopherol according to the present invention.

* Description of Major Symbols in Drawings *

110: isophyllitol infusion pump

120: isofitol storage tank (w / balance)

130: solvent supply pump 200: pressure condensation reactor

210: mixer 220: heat exchanger

230: Dean Stark 240: Pressure regulating valve

250: flush valve 270: reactor heater

300: sampling valve 310: catalyst inlet

Hereinafter, the present invention will be described in more detail with reference to the accompanying drawings.

According to the present invention, DL-α-tocopherol is the main catalyst MX ₂ (wherein M is a divalent metal ion such as Zn, Fe or Sn, and X is a halogen element such as F, Cl, Br or I). Iso-Py in the presence of one or more mixed reaction solvents selected from the group consisting of nonpolar aliphatic saturated hydrocarbons, nonpolar aromatic hydrocarbons, and some polar solvents at high temperature and high pressure using silica gel (and / or silica-alumina) as a promoter It is prepared through the condensation reaction of tol or phytol derivatives with TMHQ.

As mentioned in the above-mentioned Korean Patent Application No. 99-57483, in the case of preparing DL-α-tocopherol by condensation reaction of isopyitol or phytol derivative with TMHQ in the presence of MX ₂ and various cocatalysts, The product is a two step reaction which proceeds through the formation of an intermediate. At this time, MX ₂ mainly contributes to the formation of an intermediate as a main catalyst, the co-catalyst serves to suppress side reactions and to work with the MX ₂ catalyst to form DL-α-tocopherol in the intermediate. In particular, the cocatalyst silica gel (and / or silica-alumina) is suitable for suppressing side reactions, but isopyitol or phytol derivatives, intermediates, and DL-α-tocopherols decomposed with unreacted TMHQ on the surface of the silica gel catalyst. Since the silica gel loses activity by being adsorbed to capture the active group of the silica gel catalyst, it cannot be reused. Thus, conventionally, Bronsted acid is added to accelerate the reaction from the intermediate to DL-α-tocopherol, and decomposed isopyitol or phytol derivatives adsorbed on the surface of silica gel (and / or silica-alumina), The intermediates and DL-α-tocopherol were desorbed to regenerate the silica gel, and at the same time, the desorbed intermediate was converted to DL-α-tocopherol, but isopytol or phytol derivatives were dehydrated by Bronsted acid to decompose itself. The problem of accelerated device corrosion could not be prevented.

Therefore, in the present invention, the silica gel functions as Bronsted acid by increasing the reactor pressure to increase the reflux temperature of the solvent, thereby increasing the reaction rate by increasing the activity of the catalyst MX ₂ and silica gel and / or silica-alumina. Can be performed simultaneously so that a rapid conversion from intermediate to DL-α-tocopherol is achieved without the addition of Bronsted acid. Therefore, it is possible to minimize the amount of isopyitol or phytol derivatives consumed in the reaction by preventing self-decomposition of isopyitol or phytol derivatives by Bronsted acid, and the amount of silica gel and / or silica-alumina used. This can reduce unnecessary equipment for its regeneration and also prevent corrosion of the device by the use of Bronsted acid.

Pytol derivatives used in the present invention are represented by the following formula (1) or (2).

In the above, X is a hydroxy group, a halogen atom or an acetoxy group.

In the above, Y is a hydroxyl group, a halogen atom or an acetoxy group.

In the present invention, the amount of isopyitol or phytol derivative to TMHQ is preferably used in the range of 95 to 110 equivalents relative to 100 equivalents of TMHQ in terms of yield, and more preferably in the range of 100 to 105 equivalents.

In the present invention, the amount of the catalyst system used, that is, MX ₂ + silica gel (and / or silica-alumina) is preferably used in an amount of 5 to 20 parts by weight based on 100 parts by weight of TMHQ. This amount is considerably reduced considering that the amount of the catalyst system required to achieve the same result in the prior art is 20 to 300 parts by weight. At this time, the ratio of MX ₂ and silica gel (and / or silica-alumina) is preferably in the range of 50 to 200 parts by weight, more preferably 100 to 150 parts by weight based on 100 parts by weight of MX ₂ . This shows a good result in the production reaction of DL-α-tocopherol when the amount of catalyst used for TMHQ is used in a range in terms of catalytic amount. In the present invention, the interaction between MX ₂ and silica gel (and / or silica-alumina) This is because the DL-α-tocopherol production reaction shows excellent results when the proper ratio of action is maintained.

In the case of silica gel and / or silica-alumina used for the reaction, there is no particular restriction, but silica gel preferably has a BET surface area of 100 m ² / g or more, and silica-alumina preferably has a BET surface area of 500 m ² / g or more.

The reaction solvent used in the present invention is a non-polar aromatic solvent system such as toluene, benzene, xylene, n-heptane, mixed-heptane, n-hexane, mixed-hexane, n-octane, mixed-octane, n- Nonpolar aliphatic saturated hydrocarbon solvent systems such as decane, mixed-decane, and some polar solvents such as butyl acetate, dichloroethane, dichloromethane, ethyl acetate, methyl acetate, diethylmalonate, and the like, toluene, n-heptane, mixed-heptane and the like are preferred, and n-heptane and mixed-heptane are most preferred. The reaction solvent is used in the range of 100 to 300 parts by weight based on 100 parts by weight of TNHQ, which is a much reduced amount compared to about 700 parts by weight of the solvent used in the prior art.

In addition, the polar solvent used to wash the catalyst is methyl acetate, ethyl acetate (ethyl acetate), propyl acetate, butyl acetate, pentyl acetate, acetone, methyl ethyl ketone, diethyl ketone, methyl isopropyl ketone, methanol, ethanol, propanol , Isopropyl alcohol, butanol, pentanol, hexanol, heptanol and octanol.

The condensation reaction temperature of the isopyitol or phytol derivative and TMHQ is preferably in the range of about 100 to 170 ° C, and the reaction pressure is in the range of 0.5 to 3.0 KG. If the reaction temperature is less than 100 ℃ the reaction rate is too slow to perform a long time operation, if it exceeds 170 ℃ the decomposition rate of the reaction material isopyitol or phytol derivatives is accelerated to increase the side reactions There is a problem that the conversion rate of the TMHQ is reduced. In addition, when the reaction pressure is less than 0.5KG, there is a problem that the reaction temperature according to the vapor pressure of the solvent used is lowered, and when it exceeds 3.0KG, the reaction temperature is increased to 170 ℃ or more to the There is a problem that the decomposition rate is increased. At this time, the reaction time is preferably about 2 to 10 hours (including isotitol addition time), and most preferably 4 to 8 hours.

1 is a process diagram schematically showing one embodiment of a process for producing DL-α-tocopherol according to the present invention.

In this embodiment, the isopyitol or phytol derivatives are weighed from the storage tank 120 and then a constant amount of isopyitol or phytol derivative is supplied to the pressure condensation reactor 200 by the injection pump 110. It is configured to be. In the case of TMHQ, the total amount of TMHQ required for the reaction is dissolved in a solvent and then supplied through a solvent supply pump 130 or measured as desired in the form of a solid powder from the outside and then manually supplied. In this case, TMHQ is introduced into the pressure condensation reactor 200 together with the main catalyst MX ₂ and the cocatalyst silica gel (and / or silica-alumina) in the presence of a reaction solvent. The pressure condensation reactor is provided with a jacket heater reactor 270 is configured to control the temperature in the reactor. At this time, a mixer 210 is installed inside the reactor in order to enhance the stirring effect of the solvent, the reactant isopyitol or the phytol derivative / TMHQ and the catalyst. In addition, the reaction solvent heated by the reactor heater 270 is vaporized and transferred to the heat exchanger 220 installed on the pressure condensation reactor 200, and the vapor pressure of the vaporized solvent is the top of the heat exchanger 220. Or it is configured to be adjusted to the desired pressure by the pressure control valve 240 installed in the periphery. Thereafter, the water generated during the reaction with the reaction solvent is also supplied to Dean Stark 230 installed under the heat exchanger 220, and water is also separated therefrom and removed through the bottom of Dean Dean 230. At this time, the cooled reaction solvent is again transferred to the pressure condensation reactor 200 is used continuously.

First, 5-20 parts by weight of MX ₂ + silica gel (and / or silica-alumina) is added to 100 parts by weight of the TMHQ, and the mixture is added to the mixer 210 in the pressure condensation reactor 200 and mixed. At this time, the temperature in the reactor is maintained at 100 to 170 ° C. by the reactor heater 270 installed outside the reactor, and the pressure is increased to 0.5 to 3.0 KG using the pressure regulating valve 240. The amount of isopyitol or phytol derivatives in an amount of 95-110 equivalents to 100 equivalents of TMHQ is introduced into the reactor by the injection pump 110 from the storage tank 120 while being controlled at a constant flow rate. At this time, the heated solvent and water generated during the reaction are refluxed to pass through a heat exchanger 220 installed at the top of the reactor, wherein the heated solvent and water are cooled in the heat exchanger and introduced into Dean Stark 230. Thus, the water and the solvent are separated therefrom, and the solvent is recycled back to the pressure condensation reactor 200, while the heat released by cooling the solvent and the water causes the steam pressure to be generated from the heat exchanger. At this time, the generated steam pressure is to be controlled by the pressure control valve 240 to achieve a high pressure condition in the pressure condensation reactor (200).

In addition, a flush valve 250 is installed below the pressure condensation reactor 200 to separate or remove the reaction product, reactants such as isopyitol or phytol derivatives / TMHQ, and catalysts in the solvent. Then, the remaining cocatalyst, silica gel and / or silica-alumina, is washed with a polar solvent to be regenerated and recovered.

Hereinafter, the present invention will be described in more detail with reference to the following examples, but the scope of the present invention is not limited to the following examples.

Example 1

1400 g of TMHQ, 115 g of silica gel, and 98 g of ZnCl ₂ were added to a 20 L compression condenser, and 2800 g of n-heptane was added thereto, followed by stirring. Then, the reactor was heated to reflux n-heptane while maintaining the temperature at 135 ° C. and the pressure at 1.0 KG, and then 2837.8 g of isopyitol was pumped through the isopyitol injection pump at a rate of 472.9 g / hr. Injected into. After completion of the injection of isopyitol, the reaction was further performed for about 1 hour, and then the progress of the reaction was confirmed by gas phase chromatography. As a result, it was confirmed that the TMHQ conversion rate is 98.2%, the purity of the resulting DL-α-tocopherol is 98.5%.

Example 2

1400 g of TMHQ, 92 g of silica gel, and 98 g of ZnCl ₂ were added to a 20 L compression condenser, and 2,800 g of n-heptane was added thereto and stirred. Then, the reactor was heated to reflux n-heptane while maintaining the temperature at 140 ° C. and the pressure at 1.8 KG, and then 2837.8 g of isopyitol was injected into the reactor at a rate of 472.9 g / hr through an isopyitol injection pump. It was. After completion of the injection of isopyitol for about 2 hours, the reaction progress was confirmed by gas phase chromatography. As a result, it was confirmed that the TMHQ conversion rate is 98.03%, the purity of the resulting DL-α-tocopherol is 96.7%.

The present invention relates to a method for preparing DL-α-tocopherol under conditions of high temperature and high pressure using MX ₂ and silica gel (and / or silica-alumina) as a mixed catalyst, and conventional DL-α-tocopherol production methods and In comparison, DL-α-tocopherol can be obtained in high yield and high purity by drastically reducing side reactions generated during condensation reaction of isopyitol or phytol derivatives with TMHQ. In addition, by increasing the activity of silica gel (and / or silica-alumina), not only the amount used is reduced, but the use of Bronsted acid eliminates the need for additional processes for continuous reuse of silica gel and solves the problem of device corrosion. Can be. Therefore, it has the advantage of reducing costs, facilitating process operation, and greatly reducing investment costs. Therefore, improvement effects such as high purity, high yield, and economical production of commercially important DL-α-tocopherol can be expected in the future. Can be.

Claims (11)

A method for producing DL-α-tocopherol by condensation reaction of isopyitol or phytol derivatives with TMHQ using a mixed catalyst system consisting of MX ₂ , a divalent metal halogen compound, and a cocatalyst, in the presence of a reaction solvent 0.5-3.0 KG, 100-170 ° C. using silica gel and / or silica-alumina as cocatalyst with MX ₂ (where M is Zn, Fe or Sn and X is F, Cl, Br or I) as cocatalyst Isopytol was added slowly for 2 to 10 hours in order to obtain a product, and the Bronsted acid, which was characterized in that the remaining cocatalyst, silica gel and / or silica-alumina, was recovered by washing with a polar solvent. Method for producing high purity DL-α-tocopherol in high yield without using. The method of claim 1, wherein the reaction solvent is one or more selected from the group consisting of aliphatic saturated hydrocarbons, aromatic hydrocarbons and polar solvents, high purity DL-α-tocopherol without the use of Bronsted acid Method of preparation in yield. The method of claim 2, wherein the aromatic hydrocarbon is toluene, benzene or xylene, and the aliphatic saturated hydrocarbon is n-heptane, mixed-heptane, n-hexane, mixed-hexane, n-octane, mixed-octane, n-decane Or mixed-decane, and wherein the polar solvent is butyl acetate, dichloroethane, dichloromethane, ethyl acetate, methyl acetate or diethylmalonate, high purity DL-α-tocopherol without the use of Bronsted acid How to prepare in high purity. The method of claim 1, wherein the polar solvent for washing the catalyst is methyl acetate, ethyl acetate, propyl acetate, butyl acetate, pentyl acetate, acetone, methyl ethyl ketone, diethyl ketone, methyl isopropyl ketone, methanol, ethanol, propanol High yield of DL-α-tocopherol without using Bronsted acid, characterized in that it is selected from the group consisting of isopropyl alcohol, butanol, pentanol, hexanol, heptanol and octanol Method of manufacture. The method of claim 1, wherein the phytol derivative is represented by the following Chemical Formula 1 or Chemical Formula 2, wherein the high purity DL-α-tocopherol is prepared in high yield without using Bronsted acid. Formula 1 In the above, X is a hydroxy group, a halogen atom or an acetoxy group; Formula 2 In the above, Y is a hydroxyl group, a halogen atom or an acetoxy group. The method of claim 1, wherein the amount of the MX ₂ and silica gel and / or silica-alumina is 5 to 20 parts by weight based on 100 parts by weight of TMHQ, DL-α- of high purity without using the Bronsted acid Process for preparing tocopherol in high yield. The method of claim 6, wherein the amount of the silica gel and / or silica-alumina is 50 to 200 parts by weight based on 100 parts by weight of MX ₂ , DL-α-tocopherol of high purity without using Bronsted acid Method of manufacturing in high yield. The method of claim 7, wherein the amount of the silica gel and / or silica-alumina is 100 to 150 parts by weight based on 100 parts by weight of MX ₂ , DL-α-tocopherol of high purity without using Bronsted acid Method of manufacturing in high yield. The method of claim 1, wherein the BET surface area of the silica gel used as the cocatalyst is 100m ² / g or more, and the BET surface area of silica-alumina is 500m ² / g or more, high purity without using Bronsted acid To prepare DL-α-tocopherol in high yield. The method of claim 1, wherein the isopyitol or phytol derivative is used in an amount of 95 to 110 equivalents based on 100 equivalents of trimethylhydroquinone, and the high purity of DL-α-tocopherol is obtained without using Bronsted acid. Method of preparation in yield. The method of claim 10, wherein the isopyitol or phytol derivative is used in an amount of 100 to 105 equivalents based on 100 equivalents of trimethylhydroquinone, and the high purity of DL-α-tocopherol is obtained without using Bronsted acid. Method of preparation in yield.