JP2007210912A - Method for producing acylated tocopherol and apparatus therefor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for the continuous and quick synthesis of an acylated tocopherol from a carboxylic acid anhydride and tocopherol in the absence of catalyst or adding a small amount of a condensing agent and provide an apparatus and reaction composition for the synthesis. <P>SOLUTION: The method for the continuous and quick synthesis of an acylated tocopherol from a carboxylic acid anhydride and tocopherol in high yield and selectivity comprises the use of a subcritical fluid or supercritical fluid having a temperature of 100-400°C and a pressure of 0.1-40 MPa as a reaction solvent, introduction of a substrate and the reaction solvent into a high temperature and pressure flow reactor in the absence of catalyst and the adjustment of reaction time. The invention further provides an apparatus and reaction composition for the synthesis. The invention can provide an acylated tocopherol composition having biocompatibility and useful as livestock products, foods, medicines, etc. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to an acylated tocopherol composition, a method for producing the same, and an apparatus, and more specifically, non-catalyzed and acylated tocopherol in one step using water or acetic acid in a high temperature and high pressure state, or a mixed solvent thereof as a reaction solvent. The present invention relates to a method for producing the same, an apparatus thereof and an acylated tocopherol composition. The present invention uses acylated tocopherol from carboxylic anhydride and tocopherol in one step in a short time without adding a catalyst, using water or acetic acid at a temperature of 100 to 400 ° C. and a pressure of 0.1 to 40 MPa as a reaction solvent. A method of synthesis, an apparatus thereof, and a reaction composition thereof are provided.

  Tocopherol and its derivatives are useful as feed additives, antioxidants, circulatory stimulants and cell aging delay agents in related fields such as livestock, food and medicine. It is known that acylated tocopherols, in particular tocopherol acetate, are industrially used as feed additives by blending powders with silica, for example. Usually, when synthesizing acylated tocopherol, the conventional method requires an aprotic organic solvent and an acid / base catalyst. When used in foods, pharmaceuticals, etc., the remaining organic solvent and catalyst are used for the removal. It requires a lot of labor and has problems such as being harmful to the living body as well as affecting the environment. The present invention provides a method for synthesizing an acylated tocopherol from a carboxylic anhydride and a tocopherol without using a catalyst and using only water, an apparatus for the synthesis, and a reaction composition thereof. In addition, the present invention can be applied to synthesis of chemical products, and enables to continuously produce and provide a biocompatible acylated tocopherol in a short time.

  Conventionally, a method for synthesizing acylated tocopherol from carboxylic anhydride and tocopherol has been reported (for example, Non-Patent Document 1). According to the prior art documents, tocopherol acetate is obtained in 96% yield from tocopherol using pyridine as a catalyst and a solvent (Non-patent Document 2). Moreover, it stirs for 6 hours at 36-38 degreeC by using triethylamine as a catalyst in an ethyl acetate solvent, and tocopherol acetate is obtained with a yield of 98.6% from tocopherol (patent document 1). Moreover, tocopherol acetate can be obtained in a yield of 99% from tocopherol under non-catalytic conditions or pyridine catalytic conditions by microwave heating (irradiation power 1 kW) (Patent Document 2).

On the other hand, a method for synthesizing tocopherol acetate from trimethylhydroquinone and an isophytol derivative has also been developed. For example, after synthesizing tocopherol from trimethylhydroquinone and isophytol in supercritical carbon dioxide with a solid acid such as Amberlyst A15 at a temperature of 90 ° C., a pressure of 16.5 MPa, and a reaction time of 30 minutes, the reaction is carried out with acetic anhydride for 4 hours. 68% of tocopherol acetate is obtained (Patent Document 3). Moreover, after reacting with trimethylhydroquinone and isophytyl chloride in a carbon dioxide atmosphere for 12 hours in diethyl ether using BF ₃ as a catalyst to obtain a crude tocopherol product, an excess amount of acetic anhydride is added to obtain tocopherol acetate. There is a method (Patent Document 4).

  Furthermore, tocopherol acetate was synthesized from trimethylhydroquinone and isophytyl chloride using iron powder and hydrogen chloride or iron (II) chloride as a catalyst under reflux conditions in toluene for 4 hours and then reacted with acetic anhydride for 5 hours. It is obtained with a purity of 100% (Patent Document 5). On the other hand, after synthesizing tocopherol from trimethylhydroquinone and isophytol in a low boiling point organic solvent slightly mixed with water using an aqueous solution containing zinc halide and protonic acid concentrated to 80-90% as a catalyst, Separation is removed, water is removed from the recovered catalyst aqueous solution to a predetermined number of moles, a deficient catalyst is added, the mixture is recycled to the raw material side, acylation is performed on the crude tocopherol product, and the yield of tocopherol acetate is> 97 There is a recirculation circulation type synthesis process obtained in% (Patent Document 6).

  In addition, an acetic acid aqueous solution containing zinc halide and protonic acid from trimethylhydroquinone and isophytol is used as a catalyst. After synthesizing a tocopherol / tocopherol acetate mixture at 80 ° C. for 3 hours, the crude product is separated, and the acetic acid aqueous solution containing the catalyst is prepared. Is added to the recovered catalyst from which water has been removed and recycled to the raw material side together with the recovered acetic acid. On the other hand, post-acylation is performed with the remaining catalyst and acetic anhydride to yield tocopherol acetate in a yield> 97. There is also a recirculation circulation type synthesis process obtained in% (Patent Documents 7 and 8).

  Here, in the above prior art documents, an organic solvent in addition to a catalyst such as an organic base, a Lewis acid, and a solid acid is indispensable for the synthesis of tocopherol acetate, except when microwaves are used. Here, in the case of general acylation, it is said that the acylation is optimally performed at room temperature and the high temperature condition is unsuitable because impurities are generated at high temperature conditions and the selectivity is reduced. (Patent Documents 9 and 10). On the other hand, regarding the possibility of water as a solvent in acylation, a method of adding an acylating agent to a crude product and acylating under anhydrous conditions is generally used, and water is said to inhibit acylation ( In Patent Document 11) and a certain Patent Document, water is listed as a solvent, but it is not actually used (see Patent Documents 9 and 10).

However, there is an example in which the correlation between the catalytic activity for the aldol reaction and the stability of Lewis acid in water is systematically compared for each element and suggests the applicability to other reactions (Non-patent Document 15). . Furthermore, when Bi (OTf) ₃ is a catalyst, there is a document in which a wet organic solvent containing water that has not been dehydrated promotes the reaction and an improvement in yield is observed (non-patent document). 4). Therefore, the effectiveness of water as a solvent for acylation has not been clear so far and the use of water has not been practiced. On the other hand, it has been reported that under the solvent-free conditions when Bi (OTf) ₃ is used as a catalyst, the yield decreases and an organic solvent is required (Non-patent Document 4).

  After the reaction, the post-treatment is carried out by adding a neutralizing agent to the reaction mixture and neutralizing the reaction mixture, adding an extraction solvent and water or saturated saline, and separating the solution. The layer is then subjected to a process of drying, solvent removal, distillation or rectification to obtain the desired product. In addition to water, the layer is a catalyst, organic solvent, acetic acid, substrate, product, by-product. In addition, a mixture of inorganic complex reaction system components is contained. Here, when the separation of the catalyst from the aqueous layer is easy, it is recovered and regenerated and reused, but when the separation is difficult, it is discarded and disposed as it is (FIG. 2). If the water layer does not contain catalyst or organic solvent and contains only water, acetic acid, and product, as in the case of acylation in non-catalyst / high temperature / high pressure water, the product is separated by decantation. It is possible to separate into water and glacial acetic acid by performing azeotropic distillation in which a substance that forms an azeotrope is added to the aqueous layer (Patent Document 5). This means that this method makes it possible to regenerate water and is an environment-reducing type process compared to the normal method (FIG. 3).

JP-A-5-170757 JP 2002-47284 A US Pat. No. 5,523,420 U.S. Pat. No. 2,723,278 U.S. Pat. No. 3,789,086 Japanese Patent Laid-Open No. 10-195066 JP 2001-261670 A US Patent 6,239,294 B1 Specification JP 9-169690 A Japanese Patent Laid-Open No. 9-176081 US Pat. No. 6,005,122 US Pat. No. 5,980,696 J. G. Baxter et al., J. Am. Chem. Soc., 918 (1943) N. Cohen, C. G. Scott, C. Neukom, R. J. Lopresti, G. Weber, G. Saucy, Helv. Chim. Acta, 1981, 64, 1158 S. Kobayashi, S. Nagayama, T. Busujima, J. Am. Chem. Soc., 1998, 120, 8287 J. Otera, A. Orita, C. Tanahashi, A. Kakuta, Angrew. Chem. Int. Ed., 2000, 39, 2877

  Thus, in the conventional method, in the case of acylation, a catalyst and an organic solvent are required. Therefore, in the separation operation after the reaction, removal of the catalyst, the organic solvent and the carboxylic acid is necessary for the product quality. The water layer after the operation tends to become waste, causing a problem of waste liquid. Furthermore, in consideration of the influence on the environment and harmfulness to living organisms, and the safety of foods and pharmaceuticals that are orally administered by humans, higher separation of catalysts and organic solvents is required. The cost required for these advanced separations is comparable to that of the synthesis operation, and it is desirable not to use a catalyst and an organic solvent. In view of the above, in this technical field, a simple, low-cost, environmentally-reduced synthesis process allows easy separation and high-level separation of reaction system components, leaving no catalyst or organic solvent, and biocompatibility. There has been a strong demand for a synthesis method that enables the continuous synthesis of acyl compounds having an.

  Under such circumstances, in view of the above prior art, the present inventors have been able to synthesize new acylated tocopherols continuously by a low-cost, environmentally friendly and simple high-speed synthesis process. As a result of intensive research aimed at developing a method, high-temperature, high-pressure water, subcritical water, or supercritical water is used as a reaction solvent to synthesize acylated tocopherol from carboxylic anhydride and tocopherol without using a catalyst. After finding out what can be done and further research, the present invention has been completed. An object of the present invention is to provide a method for continuously synthesizing an acylated tocopherol from a carboxylic anhydride and a tocopherol without using a catalyst under a short reaction condition, an apparatus therefor, and a reaction composition thereof. .

  The present invention for solving the above-mentioned problems is an acylated tocopherol characterized in that the reaction composition synthesized by the reaction of carboxylic anhydride and tocopherol has no residual catalyst and organic solvent and has biocompatibility. A composition. This acylated tocopherol composition is a reaction product from a carboxylic acid anhydride and a tocopherol, and is characterized by having no catalyst and organic solvent remaining and having biocompatibility. The present invention also relates to a method for synthesizing acylated tocopherol from carboxylic anhydride and tocopherol, using a subcritical fluid or supercritical fluid in a high temperature and high pressure state as a reaction solvent, and without using a catalyst and an organic solvent, It is characterized by selectively and continuously synthesizing acylated tocopherol from an acid and tocopherol through a one-step synthesis reaction.

  In the method of the present invention, (1) an acylated tocopherol is formed from a carboxylic acid anhydride and a tocopherol in a one-step synthesis reaction using a subcritical or supercritical fluid in a high temperature and high pressure state as a reaction solvent without using an organic solvent and a catalyst. (2) using a subcritical or supercritical fluid in a high temperature and high pressure state as a reaction solvent; (3) a subcritical fluid or supercritical fluid having a temperature of 100 to 400 ° C. and a pressure of 0.1 to 40 MPa. (5) using water, acetic acid, other inorganic solvent, or organic solvent, or a mixed solvent of an inorganic solvent and an organic solvent as a subcritical fluid or supercritical fluid, (6) In a preferred embodiment, the substrate and the reaction solvent are introduced into a flow-type high-temperature and high-pressure apparatus, and the reaction time is changed in the range of 3 to 60 seconds to carry out the synthesis reaction.

  The present invention also includes a water feed pump for feeding water, a water heating coil, a high-temperature and high-pressure flow cell, a reactant feed pump for feeding a substrate, a furnace body, and a reactant introduction for introducing the reactant into the furnace body. An acylated tocopherol synthesizer comprising a tube, a drain line for discharging a reaction solution, a cooling flange, and a back pressure valve for setting a pressure. Furthermore, the present invention, after acylation by the above method, decantation by injecting water into the recovered aqueous solution, separating into an oil / water bilayer solution, and separating and recovering the oil layer containing acylated tocopherol, Is a simple continuous separation method for reaction system components, characterized in that acetic acid and water are separated and recovered by azeotropic distillation.

Next, the present invention will be described in more detail.
The present invention selectively synthesizes an acylated tocopherol of Chemical Formula 3 from a carboxylic acid anhydride of Chemical Formula 1 and a tocopherol of Chemical Formula 2 in a one-step reaction process without adding a catalyst and in a short reaction condition. (Characteristic 4). In the present invention, a subcritical fluid or a supercritical fluid having a temperature of 100 to 400 ° C. and a pressure of 0.1 to 40 MPa is used as the reaction solvent, and preferably subcritical water is used. The reaction conditions are preferably a temperature of 200 to 250 ° C., a pressure of 5 MPa, a reaction time of 60 seconds or less, preferably 3 to 60 seconds, and more preferably about 10 seconds. Adjusted. In the formulas of Chemical Formula 1, Chemical Formula 3, and Chemical Formula 4, R is an alkyl group and a substituent containing a hetero atom other than the alkyl group.

  In the present invention, the substrate and the reaction solvent are introduced into a reaction vessel and a synthesis reaction is carried out in a predetermined reaction time. In this case, as the reactor, for example, a batch-type high-temperature / high-pressure reaction vessel and a continuous flow-type high-temperature / high-pressure reactor can be used, but the present invention is particularly limited to the types of these reactors. It is not something.

  In the method of the present invention, the subcritical fluid and supercritical fluid in the high temperature and high pressure state are used as the reaction solvent. Specifically, subcritical carbon dioxide (normal temperature or higher, 0.1 MPa or higher), subcritical water is used. (100 ° C. or higher, 0.1 MPa or higher), subcritical methanol (100 ° C. or higher, 0.1 MPa or higher), subcritical ethanol (100 ° C. or higher, 0.1 MPa or higher), supercritical carbon dioxide (34 ° C. or higher, 7. 38 MPa or more), supercritical water (375 ° C. or more, 22 MPa or more), supercritical methanol (239 ° C. or more, 8.1 MPa or more), supercritical ethanol (241 ° C. or more, 6.1 MPa or more), a mixed solvent in the same state It is illustrated and subcritical water (200-250 degreeC, 5 Mpa or more) is used suitably. As the reaction solvent, an organic solvent or an inorganic solvent other than those described above can be contained in any ratio. Specifically, as the organic solvent, a reaction solution containing acetone, acetonitrile, tetrahydrofuran or the like, and as the inorganic solvent, acetic acid is used. It is also possible to substitute a reaction solution containing ammonia or the like.

  In the present invention, by adjusting the composition of the reaction solvent of the subcritical fluid and supercritical fluid, the temperature and pressure conditions, the type and amount of the substrate used, and the reaction time, the reaction product can be efficiently produced in a short time. Can be synthesized. In the present invention, for example, by introducing a substrate and a reaction solvent into a flow-type high-temperature and high-pressure apparatus and changing their reaction time within 60 seconds, preferably within a range of 3 to 60 seconds, Products can be synthesized. The reaction conditions can be appropriately set depending on the starting material used, the type of the desired reaction product, and the like.

  In the method of the present invention, the synthesis of acylated tocopherol from carboxylic acid anhydride and tocopherol, which has been conventionally carried out in the presence of a catalyst, can be carried out continuously at a high speed and without a catalyst. The required process can be made more efficient. In addition, since the catalyst of the present invention is not used at all in the method of the present invention, there is no need for post-treatment and disposal such as neutralization treatment and detoxification treatment of the solution after the reaction, and environmental load reduction can be achieved. is there. Furthermore, since the separation process after the reaction is only a stationary separation operation, there is no need to separate and recover the catalyst and the organic solvent, and product separation becomes easy. According to the present invention, the corresponding acylated tocopherol can be synthesized in 99% in a short time of about 10 seconds without addition of a catalyst. The synthesis method of the present invention is useful as a method for efficiently and continuously producing a large amount of acylated tocopherol having biocompatibility, which can be used in livestock, foods, pharmaceuticals and the like.

  Conventionally, examples of acylation using a lipase or a catalyst using a subcritical fluid such as carbon dioxide or a supercritical fluid have been reported. However, there is no example demonstrating that acylated tocopherol can be synthesized in high yield from a carboxylic acid anhydride and tocopherol in a non-catalytic subcritical water process. The effectiveness of the present invention has been demonstrated for the first time by the present inventors. Moreover, the acylated tocopherol synthesized from the carboxylic acid anhydride and tocopherol by the conventional method had a problem of remaining catalyst and organic solvent, but the reaction composition synthesized from the carboxylic acid anhydride and tocopherol in the present invention. Has no residual catalyst and organic solvent and is biocompatible, and the acylated tocopherol composition of the present invention has advantages not found in conventional products.

  In the present invention, in order to realize a synthesis reaction of carboxylic anhydride and tocopherol under non-catalytic conditions, for example, a solution in which a substrate is previously dissolved in a solvent is fed, and the reaction progress in a subcritical fluid or supercritical fluid is determined. It is also possible to use a flow-type high-temperature high-pressure infrared spectroscopic in-situ measurement apparatus (FIG. 5) that is observed by infrared spectroscopic analysis with a high-temperature high-pressure infrared flow cell (FIG. 4). However, it is better to replace the high-temperature and high-pressure infrared flow cell with a windowless high-temperature and high-pressure flow cell (FIG. 6) and arrange the piping so that the reactant flow directly contacts the supercritical fluid flow. There is no problem such as leakage near the cell window in the flow cell, and the synthesis can be performed in a short time at a higher flow rate. For these reasons, in the examples described later, an apparatus equipped with this windowless high-temperature and high-pressure flow cell was used.

  Here, the windowless high-temperature and high-pressure flow cell main body (FIG. 6) can be fixed to a temperature sensor sheath (12 in FIG. 7) described below by, for example, screwing a commercially available SUS316 cloth 1. Can be built. Without measuring the temperature of the furnace atmosphere, the temperature sensor sheath fixing screw and the male screw 3 are screwed to indicate the cell temperature. The pipe 4 of SUS316 is connected to the cross 1 with a taper screw 2 with a one-ring ferrule on the cross 1. Of course, the cloth 1 can also be used as a tee by closing one flow path with an end screw.

  FIG. 7 is a reactor body portion of a flow-type high temperature / high pressure reactor equipped with a windowless high temperature / high pressure flow cell, which is a main body of the reactor. If this is installed in the shaded position of the flow-type high-temperature and high-pressure fluid in-situ infrared spectrometer of Fig. 5, the infrared spectroscopy cannot be measured, but the subcritical / supercritical fluid contact type with variable temperature, pressure and flow rate. It can be used as a synthesis reaction apparatus. In this case, the reaction is observed by collecting the discharged aqueous solution, performing quantification from a calibration curve using a pure product by GC-FID, and performing qualitative analysis by GC / MS. be able to. Further, quantitative and qualitative analysis can be performed by NMR.

  Next, the flow-type high-temperature and high-pressure reactor main body shown in FIG. 7 will be described. After passing through the tube coil 9, it is introduced into a high temperature / high pressure flow cell 14 supported and fixed to a temperature sensor sheath 12 in which a temperature sensor 11 is inserted in a high temperature / high pressure state. On the other hand, the reactant is fed from the reactant feed pump 6, passes through the cooling flange 8, and then sent to the furnace body 13. After passing through the coiled reactant introduction tube 10, it is introduced into a high-temperature and high-pressure flow cell 14 fixed to the temperature sensor sheath 12. Further, the washing water is fed by the pump 7, passes through the pipe 16, is introduced into the tee 18, and is used for washing. The solution that has passed through the high-temperature and high-pressure flow cell passes through the piping 17, then passes through the cooling flange 8, and passes outside the furnace body while being air-cooled. Thereafter, the discharged liquid from the back pressure valve 19 for which the pressure is set is collected and used as a sample. Here, in order to eliminate the influence of heating of the discharge liquid containing the reactants and products, rapid heating is performed, and the piping of the reactant introduction line 10 and the discharge liquid line 17 is made as short as possible so that the water heating coil It is desirable to make 9 as long as possible. The present invention is not limited to these, and any reaction apparatus having the same effect as these can be used in the same manner.

The following effects are exhibited by the present invention.
(1) An acylated tocopherol can be synthesized continuously at high speed from a carboxylic acid anhydride and a tocopherol.
(2) A synthesis process without using a catalyst and an organic solvent can be realized.
(3) Therefore, it is possible to provide a highly safe biocompatible acylated tocopherol composition that is free from residual catalyst and organic solvent and is not harmful to the living body.
(4) Since acylated tocopherol does not dissolve in water, water is injected into the discharged oil-water dispersion aqueous solution to separate into two layers of oil and water while washing, and high-purity products are easily recovered. it can.
(5) As a new mass production process of acylated tocopherol having biocompatibility useful as livestock, food and medicine, it is possible to provide a new production technique that can replace the existing production process.

  EXAMPLES Next, although this invention is demonstrated concretely based on an Example, this invention is not limited at all by the following Examples.

Examples 1 and 2
In this example, 2,6-dimethylphenol was used to determine the conditions for acylation from tocopherol to tocopherol acetate. The effect of temperature was examined by keeping the synthesis conditions constant under the conditions of no catalyst, a predetermined temperature, a pressure of 5 MPa, and a residence time of 9.9 seconds. First, pure water is sent at a flow rate of 5.0 ml / min to the apparatus in which the main body (main part) of the flow-type high-temperature and high-pressure reactor shown in FIG. Submerged and set to a predetermined temperature and a pressure of 5 MPa to obtain subsupercritical water. Thereafter, toluene was added as an internal standard (5 mol% of 2,6-dimethylphenol), and 0.5 ml / min of a mixed solution of acetic anhydride / 2,6-dimethylphenol (molar ratio: 1.1 / 1) was pumped. The solution was fed (concentration of aqueous solution after mixing: 0.53 mol / kg).

  1 ml of the aqueous solution discharged from the back pressure valve 40 minutes after the substrate feeding was collected. When the internal volume of the pipe from the heating furnace to the back pressure valve outlet was the reaction volume, the reaction time was 9.9 seconds. 1 ml of acetone was added to 1 ml of the collected aqueous solution and shaken, and the composition was determined by GC / MS analyzer (HP 6890, Hewlett Packard, column HP-5, inlet temperature 150 ° C., initial column temperature 60 ° C. (retention time 2 Min), a heating rate of 10 ° C./min, and a final column temperature of 250 ° C. (holding time of 2 minutes)). In addition, quantification and qualitativeness in the presence of commercially available reagents are GC-FID (GC6890, Agilent DB-WAX, inlet temperature 230 ° C., split ratio 5.61, initial column temperature 50 ° C. with toluene as an internal standard ( Holding time 0.5 minutes), temperature rising rate 20 ° C./min, final column temperature 230 ° C. (holding time 3 minutes)).

  Table 1 shows the results of acylation of 2,6-dimethylphenol and tocopherol. As a result of investigation at two temperatures of 200 ° C. and 250 ° C., the yields of 2,6-dimethylphenol acetate were 47% and 97%, respectively, and the selectivity was 100% for both (Table 1, FIG. 8). In addition, although the obtained product aqueous solution is cloudy in an oil-water dispersion state, water is injected at 20 ml / min for 3 minutes and decanted to form an oil-water two-layer solution, and the upper oil layer does not contain acetic acid 2, An aqueous acetic acid solution was obtained from 6-dimethylphenol in the lower aqueous phase (confirmed by GC). This means that when the product does not dissolve in water, it is possible to separate the product and the aqueous acetic acid solution by changing water into two layers by injecting water further into the oil-water dispersion aqueous solution after completion of the reaction. Show. Since an acetic acid aqueous solution does not contain a catalyst or organic solvent, it can be fractionated into water and glacial acetic acid by azeotropic distillation by adding a compound that forms an azeotropic compound with acetic acid (for example, tertiary butyl acetate). Therefore, it is not necessary to perform rectification that requires enormous energy.

Example 3
In this example, based on the knowledge of Examples 1 and 2, it was carried out under the conditions of no catalyst, temperature 250 ° C., pressure 5 MPa, residence time 9.9 seconds with respect to tocopherol. Here, the tocopherol was used in the α form having the highest antioxidant power, but it can also be applied to other β forms, γ forms, δ forms and mixed tocopherols.

  First, pure water is sent at a flow rate of 5.0 ml / min to the apparatus in which the main body (main part) of the flow-type high-temperature and high-pressure reactor shown in FIG. 7 is installed in the flow-type high-temperature and high-pressure fluid in-situ infrared spectrometer shown in FIG. Submerged and set to a predetermined temperature and a pressure of 5 MPa to obtain subsupercritical water. Thereafter, toluene was added as an internal standard (5 mol% of tocopherol), and 0.5 ml / min of a mixed solution of acetic anhydride / tocopherol / acetic acid (molar ratio: 1.1 / 1/1) was pumped (after mixing). Aqueous solution concentration: 0.53 mol / kg). 1 ml of the aqueous solution discharged from the back pressure valve 40 minutes after the substrate feeding was collected. When the internal volume of the pipe from the heating furnace to the back pressure valve outlet was the reaction volume, the reaction time was 9.9 seconds.

  1 ml of acetone was added to 1 ml of the collected aqueous solution and shaken, and the composition was determined by GC / MS analyzer (HP 6890, Hewlett Packard, column HP-5, inlet temperature 150 ° C., initial column temperature 60 ° C. (retention time 2 Min), a heating rate of 10 ° C./min, and a final column temperature of 250 ° C. (holding time 2 minutes)), and the obtained mass spectrum was confirmed with a Willy database with a concordance of 90% or higher. In addition, quantification and qualitativeness in the presence of commercially available reagents are GC-FID (GC 6890, Agilent DB DB-WAX, inlet temperature 230 ° C., split ratio 5.61, initial column temperature 50 ° C. with toluene as an internal standard ( Holding time 0.5 minutes), temperature rising rate 20 ° C./min, final column temperature 230 ° C. (holding time 3 minutes)).

  As a result, tocopherol acetate was obtained with a yield of 99% and a selectivity of 100% (Table 1, FIG. 8). The resulting aqueous solution of the product is clouded in an oil-water dispersion state, but when water is injected at 20 ml / min for 3 minutes and decanted, an oil-water two-layer solution is formed, and tocopherol acetate containing no acetic acid is added to the upper oil layer. An aqueous acetic acid solution was obtained in the lower aqueous phase (confirmed by GC). This means that when the product does not dissolve in water, it is possible to separate the product and the aqueous acetic acid solution by changing water into two layers by injecting water further into the oil-water dispersion aqueous solution after completion of the reaction. Show. Since an acetic acid aqueous solution does not contain a catalyst or organic solvent, it can be fractionated into water and glacial acetic acid by azeotropic distillation by adding a compound that forms an azeotropic compound with acetic acid (for example, tertiary butyl acetate). Therefore, it is not necessary to perform rectification that requires enormous energy.

  From the above examples, it has been clarified that acylated tocopherol can be synthesized in high yield without catalyst using high-temperature and high-pressure water as a reaction solvent. After acylation, water is poured into the recovered aqueous solution, followed by decantation. After separation into an oil / water bilayer solution, an oil layer containing acylated tocopherol is separated and recovered, while acetic acid and water are co-recovered from the aqueous layer. It became clear that a simple continuous separation method of reaction system components separated and recovered by boiling distillation can also be carried out.

  As described above in detail, the present invention uses a high-temperature and high-pressure fluid as a reaction solvent, a method for synthesizing acylated tocopherol without using an organic solvent from a carboxylic acid anhydride and tocopherol, its apparatus, and its reaction composition. In the conventional method, the synthesis of acylated tocopherol from tocopherol and carboxylic anhydride had to add a catalyst to an organic solvent and carry out the reaction for several hours. By using a fluid or a supercritical fluid as a reaction solvent, it is possible to synthesize acylated tocopherol continuously at a high speed without using a catalyst and without using an organic solvent. This brings about the merit that the acylated tocopherol having biocompatibility useful as livestock, food and medicine can be continuously produced in a large amount in a short time. After acylation, water is poured into the recovered aqueous solution, followed by decantation. After separation into an oil / water bilayer solution, an oil layer containing acylated tocopherol is separated and recovered, while acetic acid and water are co-recovered from the aqueous layer. Glacial acetic acid and water can be separated and water can be recycled by a simple continuous separation method of reaction system components separated and recovered by boiling distillation. Therefore, in the present invention, it is possible to compress the initial cost and the running cost of the process by simplifying the synthesis / separation process. Furthermore, post-treatment of the neutralization treatment is unnecessary, and environmentally conscious production becomes possible. The present invention can replace an existing production process as providing a new mass production process of acylated tocopherol having biocompatibility useful as livestock, food and medicine.

The acylation of tocopherol using a catalyst / organic solvent is shown. The post-process flowchart of acylation using a catalyst and an organic solvent is shown. The post-process flowchart of acylation using a non-catalyst and a water solvent is shown. 1 shows a high temperature high pressure infrared flow cell. 1 shows a flow-type high-temperature and high-pressure fluid in-situ infrared spectrometer used in the examples. 1 shows a high temperature and high pressure flow cell without a window. The main part of the flow-type high temperature / high pressure reactor used in the examples is shown. A comparison of acylation of 2,6-dimethylphenol and tocopherol in the examples is shown.

Explanation of symbols

1 Tee or cloth (one side opening φ4mm threaded)
2 φ4mm × 5.0mmL hexagon screw 3 Male screw with one ring ferrule 4 SUS316 tube 5 Water feed pump 6 Reactant feed pump 7 Washing water feed pump 8 Cooling flange (cooling water circulates)
9 Water heating coil 10 Reactant introduction pipe 11 Temperature sensor 12 Temperature sensor sheath 13 Furnace body 14 High-temperature high-pressure flow cell (Tee type for normal temperature rise, cross-type for rapid temperature rise)
15 ZnSe window 16 Solvent introduction pipe 17 Discharge pipe 18 Tee 19 Back pressure valve 21 Aqueous solution 22 Washing water 23 Aqueous solution pump 24 Cleaning pure water feed pump 25 Furnace heating system 26 Furnace 27 High-temperature high-pressure infrared flow cell 28 Cooling water (inlet) )
29 Cooling water (exit)
30 Back pressure valve 31 Discharged aqueous solution receiver 32 Movable mirror 33 Movable mirror 34 Interferometer 35 Light source 36 Infrared laser 37 MCT light receiver 38 TGS light receiver 39 Analysis monitor

Claims (8)

  An acylated tocopherol composition characterized in that a reaction composition synthesized by a reaction of carboxylic anhydride and tocopherol has no compatibility with a catalyst and an organic solvent and has biocompatibility.   A process for synthesizing an acylated tocopherol from a carboxylic anhydride and a tocopherol, wherein a subcritical or supercritical fluid in a high temperature and high pressure state is used as a reaction solvent.   The method according to claim 2, wherein in the above method, acylated tocopherol is selectively synthesized from carboxylic anhydride and tocopherol by a one-step synthesis reaction without using a catalyst.   The method according to claim 2 or 3, wherein a subcritical fluid or supercritical fluid having a temperature of 100 to 400 ° C and a pressure of 0.1 to 40 MPa is used as a reaction solvent.   The method according to claim 2 or 3, wherein water, acetic acid, other inorganic solvent, or organic solvent, or a mixed solvent of an inorganic solvent and an organic solvent is used as the subcritical fluid or supercritical fluid.   The method according to claim 2 or 3, wherein the synthesis reaction is carried out by introducing a substrate and a reaction solvent into a flow-type high-temperature and high-pressure apparatus and changing the reaction time in the range of 3 to 60 seconds.   Water feed pump for feeding water, coil for water heating, high-temperature and high-pressure flow cell, reactant feed pump for feeding substrate, furnace body, reactant introduction pipe for introducing reactant into the furnace body, discharging reaction solution An acylated tocopherol synthesizer comprising a drain line for cooling, a cooling flange, and a back pressure valve for setting pressure.   After acylation by the method according to claim 2 or 3, water is injected into the recovered aqueous solution and decanted, and after separation into an oil / water bilayer solution, an oil layer containing acylated tocopherol is separated and recovered, while water A simple continuous separation method of reaction system components characterized in that acetic acid and water are separated and recovered from the bed by azeotropic distillation.

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