JP2007210911A - Method for producing polyacyl compound and apparatus therefor - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for the continuous and quick synthesis of a polyacyl compound from a carboxylic acid anhydride and a polyhetero-hydride in high yield without using a catalyst while adjusting the acylation number and provide an apparatus and reaction composition for the synthesis. <P>SOLUTION: The method for the continuous and quick synthesis of a polyacyl compound from a carboxylic acid anhydride and a polyhetero-hydride in high yield while adjusting the acylation number 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 various conditions comprising the temperature and the amount of the carboxylic acid anhydride. The invention further provides an apparatus and reaction composition for the synthesis. The invention can provide a polyacyl compound composition having biocompatibility and useful as perfume, medicine, food, etc. <P>COPYRIGHT: (C)2007,JPO&INPIT

Description

  The present invention relates to a polyacyl compound composition, a method for producing the same, and more specifically, and more specifically, a polyacyl compound is produced in a single step without using a high temperature and high pressure water or acetic acid or a mixed solvent thereof as a reaction solvent. Method, apparatus thereof, and acyl compound composition. In the present invention, water or acetic acid at a temperature of 100 to 400 ° C. and a pressure of 0.1 to 40 MPa is used as a reaction solvent, and a polyacyl compound is converted from a carboxylic anhydride and a polyheterohydride in one step in a short time without adding a catalyst. Thus, a method for continuously synthesizing and a reaction composition thereof are provided. Here, examples of the hetero atom in the polyheterohydride include oxygen, nitrogen, and sulfur, which correspond to polyol, polyamine, and polythiol, respectively.

  Polyacyl compounds are particularly useful in the fields of fragrances, pharmaceuticals, foods and the like because they improve and improve the functionality of raw materials and substrates, and further add added value. Usually, when synthesizing a polyacyl compound, the conventional method requires an acid / base catalyst in addition to the aprotic organic solvent. For example, when used in foods and pharmaceuticals, the remaining organic solvent and catalyst are The removal requires a large amount 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 a polyacyl compound from a carboxylic anhydride and a polyheterohydride such as a polyol, polyamine, polythiol, etc., without using a catalyst, and using only water, an apparatus therefor, and a reaction composition thereof. It can be applied not only to fragrances, pharmaceuticals and foods, but also to chemical synthesis, and enables polyacyl compounds to be produced and provided in large quantities efficiently in a short time.

Various methods for synthesizing polyacyl compounds from carboxylic anhydrides and polyheterohydrides, polyols, polyamines, polythiols and the like have been reported (for example, Non-Patent Document 1). Here, if a technique for synthesizing a polyacyl compound from a polyol and a carboxylic anhydride is completed, it is usually possible to synthesize a polyacyl compound from other polyheterohydrides such as polyamines and polythiols. There are numerous reports of techniques for synthesizing polyacyl compounds. However, in the conventional method, there is only a method for polyacylating all heterohydrogens, and a method for selectively polyacylating while adjusting the number of acylation has not been reported (FIG. 1). In FIG. 1, R, R _n and R _{n + 1} are an alkyl group and a substituent containing a hetero atom other than the alkyl group, Q _i is a hetero atom or a substituted hetero atom, and specifically, oxygen (O), sulfur ( S), hydrogen nitride (NH), alkyl-substituted nitrogen (NR ′). According to the prior art document, in the synthesis method of the polyacyl compound, for example, CoCl ₃ (Non-patent document 4), Me ₃ SiCl (a) of Non-patent document 5 and a catalyst in a solvent-free or aprotic organic solvent can be used. b)), Bu ₃ P (Non-Patent Document 6), pyridine (Non-Patent Document 8), and the like, which have been bases, have been used. In addition, the discovery of DMAP that activates an acyl group through the formation of a stable acyl intermediate and its application were regarded as innovative technologies (a) and b) of Patent Document 9).

However, since DMAP uses one or more equivalents of amine, metal triflate, which is a Lewis acid, has been proposed. Me ₃ SiOTf (Non-patent Document 10), Sc (OTf) ₃ (Patent Documents 1, 2 and Non-Patent Documents) Patent Document 11), In (OTf) ₃ (Non-Patent Document 12), Bi (OTf) ₃ (Non-Patent Document 13), and Sc (NTf) ₃ (Non-Patent Document 14) give polyacyl compounds in high yield. It was shown that. Furthermore, V (OTf) ₃ did not show catalytic activity, but its oxo compound V (O) (OTf) ₂ was found to have catalytic activity, and attention was paid to catalytic activation of V = O. (Patent Literature 3, Non-Patent Literature 15). With these catalysts, it is reported that a polyacyl compound can be obtained with a yield of 95% or more from a secondary alcohol and a yield of 80% or more from a tertiary alcohol (FIG. 1).

  Here, in the above prior art documents, in addition to a catalyst such as an organic base, a Lewis acid, and a solid acid, an organic solvent is indispensable for polyacylation. In addition, acylation is optimally performed at room temperature because impurities are generated under high temperature conditions and the selectivity is reduced, and high temperature conditions are considered inappropriate (Patent Documents 1 and 2). On the other hand, regarding the possibility of water as a solvent in acylation, an acylating agent is generally added to a crude product from which water has been removed and acylated, and water is said to have a negative effect. In some patent documents, water is listed as a solvent, but it is not actually used (Patent Documents 1 and 2).

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 16). . 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). 13). Thus, the effectiveness of water as a solvent for acylation has not been clear so far and no water has been used. On the other hand, under the solvent-free conditions when Bi (OTf) ₃ is used as a catalyst, it is reported that the yield decreases and an organic solvent is necessary (Non-patent Document 13).

  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 composed of catalyst, organic solvent, acetic acid, substrate, product, by-product, It contains a mixture of inorganic complex reaction system components. 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 9-169690 A Japanese Patent Laid-Open No. 9-176081 US Pat. No. 6,541,659 US Pat. No. 6,005,122 US Pat. No. 5,980,696 W. Green, P. G. Wuts, Protective Groups in Organic Synthesis, 3rd ed., Wiley, New York, 1999, p150 S. Ahmad, J. Iqbal, Chem. Commun., 1987, 114 a) N. C. Braus, R. P. Sharma, J. N. Baruah, Tetrahedron Lett., 1983, 24, 1189; b) J. Org. Chem., 1987, 52, 503 E. Vedejs, N. S. Bannet, L. M. Conn, S. T. Diver, J. Org. Chem., 1993, 58, 7286 Joseph B. Lambert, Gen Tai Wang, Rodney B. Finzel, and Douglas H. Teramura, J. Am. Chem. Soc., 1987, 109. 7838 a) G. Hofle, W. Steglich, H. Vorbruggen., Angrew. Chem. Int. Ed., 1978, 17, 569, b) A. Hassner, L. R. Krepski, V. Alexanian, Tetrahedron, 1978, 34, 2069 P. A. Procopiu, S. P. D. Baugh, S. S. Flack, G. G. A. Inglis, J. Org., Chem., 1998, 63, 2342 a) K. Ishihara, M. Kubota, H. Kurihara, H. Yamamoto, J. Org. Chem., 1996, 61, 4560, b) K. Ishihara, M. Kubota, H. Kurihara, H. Yamamoto, J Am.Chem. Soc., 1995, 117, 4413 K. K. Chauhan, C. G. Frost, I. Love, D. Waite, Synlett, 1999, 1743 J. Otera, A. Orita, C. Tanahashi, A. Kakuta, Angrew. Chem. Int. Ed., 2000, 39, 2877 K. Ishihara, M. Kubota, Synlett, 1996, 265 CT. Chen, JH. Kuo, CH. Li, NB Barhate, SW. Hon, TW. Li, SD. Chao, CC. Liu, YC. Li, IH. Chang, JS. Lin, CJ. Liu and YC. Chou , Org. Lett., 2001, 3, 3729 S. Kobayashi, S. Nagayama, T. Busujima, J. Am. Chem. Soc., 1998, 120, 8287

  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, environment-reduction-type synthesis process allows easy separation operation and high-level separation of reaction system components, and biocompatibility without remaining catalyst or organic solvent. There has been a strong demand for a synthesis method that enables continuous synthesis of acyl compounds.

  Under such circumstances, in view of the above prior art, the present inventors have developed a new synthesis method capable of continuously synthesizing the polyacyl compound by a simple high-speed synthesis process that is low in cost and friendly to the environment. As a result of intensive research with the goal of developing high-pressure, high-temperature, high-pressure water, subcritical water, or supercritical water as a reaction solvent, a polyacyl compound can be selected from carboxylic anhydride and polyheterohydride without catalyst. As a result of further research, the present invention has been completed. An object of the present invention is to provide a method for continuously synthesizing a polyacyl compound from a carboxylic anhydride and a polyheterohydride under a reaction condition in a short time without using a catalyst, an apparatus therefor, and a reaction composition thereof. is there.

  In order to solve the above-mentioned problems, the present invention provides a reaction composition synthesized by a reaction of a carboxylic anhydride and a polyhetero hydride, wherein there is no remaining catalyst and organic solvent and is biocompatible. A compound composition. This polyacyl compound composition is a reaction product from a carboxylic acid anhydride and a polyheterohydride, and is characterized by having no catalyst and organic solvent remaining and having biocompatibility. The present invention also provides a method for synthesizing a polyacyl compound from a carboxylic anhydride and a polyheterohydride, 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. A polyacyl compound is selectively and continuously synthesized from a carboxylic acid and a polyheterohydride. Here, it is preferable that the hetero atom or the substituted hetero atom in the polyhetero hydride is oxygen (O), sulfur (S), hydrogen nitride (NH), or alkyl-substituted nitrogen (NR ′). In addition, the present invention can be performed by adjusting the temperature and the amount of carboxylic anhydride depending on the primary, secondary, and tertiary skeletons adjacent to a plurality of reaction points of the substrate. A method for producing a polyacyl compound, wherein acylation is performed in the order of grades, the number of acylations is adjusted, and a polyacyl compound is selectively synthesized.

  In addition, the method of the present invention comprises (1) a one-step synthesis reaction from a carboxylic acid anhydride and a polyheterohydride without using an organic solvent and a catalyst, using a subcritical or supercritical fluid in a high temperature and high pressure state as a reaction solvent. Selectively synthesizing a polyacyl compound, (2) using a subcritical or supercritical fluid in a high temperature and high pressure state as a reaction solvent, and (3) a subcritical fluid having a temperature of 100 to 400 ° C. and a pressure of 0.1 to 40 MPa. Using a supercritical fluid as a reaction solvent, (5) using water, acetic acid, another inorganic solvent, or an organic solvent, or a mixed solvent of an inorganic solvent and an organic solvent as a subcritical fluid or supercritical fluid, (6) A preferred mode is to introduce a substrate and a reaction solvent into a flow-type high-temperature and high-pressure apparatus, and to carry out the synthesis reaction by changing the reaction time in the range of 3 to 60 seconds.

  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. A polyacyl compound 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, injects water into the recovered aqueous solution, decants it, separates it into an oil / water bilayer solution, and separates and recovers the oil layer containing the polyacyl compound. Is a simple continuous separation method of reaction system components characterized by separating and recovering acetic acid and water by azeotropic distillation.

Next, the present invention will be described in more detail.
In the synthesis of the polyacyl compound, the polyacyl compound is converted from the carboxylic acid anhydride of Chemical Formula 1 and the polyheterohydride of Chemical Formula 2 into a polyacyl compound as shown in Chemical Formula 3 in a one-step reaction process without adding catalyst. It is characterized by being synthesized selectively and continuously under the reaction conditions of In the present invention, 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 solvent for the above reaction, and subcritical water is preferably 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 formula of Chemical Formula 1, R is an alkyl group and a substituent containing a hetero atom other than an alkyl group. In the Chemical Formula 2, R _n and R _{n + 1} are a substituent containing a hetero atom other than an alkyl group and an alkyl group, Q _i is a hetero atom or a substituted hetero atom, specifically, oxygen (O), sulfur (S), hydrogen nitride (NH), alkyl-substituted nitrogen (NR ′), and x, y, and z are The number of hetero atoms each having the α-position of primary, secondary, and tertiary is shown, and the bonding order of primary, secondary, and tertiary is not limited, and the bond is shown by a dotted line. Chemical formula 3 indicates that the α-position is primary only and x number of polyacylations, Chemical formula 4 indicates (x + y) polyacylation when the α-position is primary and secondary, and Chemical formula 5 indicates that the α-position is 1, (X + y + z) polyacylations for cases 2 and 3 are shown.

  In the present invention, the substrate and the reaction solvent are introduced into a reaction vessel, and a synthesis reaction is performed in a predetermined reaction time. Therefore, 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. Not a thing.

  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, a predetermined reaction product is obtained by introducing a substrate and a reaction solvent into a flow-type high-temperature and high-pressure apparatus and changing the reaction time within 60 seconds or less, preferably 3 to 60 seconds. 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 a polyacyl compound from a carboxylic acid anhydride and a polyheterohydride, 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. 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, when no catalyst is added and the substrate is a diol in a short time of about 10 seconds, the monoacyl compound has a conversion rate of 85% or more, the selectivity is 65% or more, and the diacyl compound has a conversion rate of 99% or more. When the selectivity is 93% or more and the substrate is triol, the monoacyl compound is 91% or more, the selectivity is 59% or more, the diacyl compound is 93% or more, and the selectivity is 25% or more, and the triacyl compound is converted. The corresponding polyacyl compounds can be synthesized at 100% and a selectivity of 93% or more. The method for synthesizing a polyacyl compound of the present invention is useful as a method for efficiently and continuously producing a polyacyl compound composition having biocompatibility, which can be used for flavors, pharmaceuticals and foods, in a large amount and at a high speed. It is.

  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, by adjusting the temperature and the amount of carboxylic anhydride depending on the primary, secondary, and tertiary skeletons adjacent to multiple reaction points of the substrate under non-catalytic conditions using subcritical water as a solvent. There is no example that demonstrates acylation in the order of primary, secondary, tertiary and adjusting the number of acylation to selectively synthesize polyacyl compounds, but selective synthesis reaction of polyacyl compounds targeted by the present invention The method has been proved by the present inventors for the first time. In addition, the polyacyl compound synthesized from the carboxylic acid anhydride and the polyheterohydride by the conventional method had a problem of remaining of the catalyst and the organic solvent, but is synthesized from the carboxylic acid anhydride and the polyheterohydride in the present invention. The reaction composition has no residual catalyst and organic solvent and is biocompatible, and the polyacyl compound 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 polyheterohydride under non-catalytic conditions, for example, a solution in which a substrate is previously dissolved in a solvent is fed, and a reaction process in a subcritical fluid and a supercritical fluid is performed. It is also possible to use a flow-type high-temperature high-pressure infrared spectroscopic in-situ measurement apparatus (FIG. 5) for observing the sample by infrared spectroscopic analysis using 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 body atmosphere, the position of the temperature sensor is adjusted so as to indicate the cell temperature, and screwed with the sheath fixing screw and the male screw 3. 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 and high pressure reactor equipped with a windowless high temperature and high pressure flow cell, and is a reactor main body. 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 quantitative analysis 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 of FIG. 7 will be described. Water is fed from the water feed pump 5, passes through the cooling flange 8, and then sent to the furnace body 13. 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 that has set the pressure is collected and used as a sample. Here, in order to eliminate the influence of heating of the effluent containing the reactants and products, rapid heating is performed, the piping of the reactant introduction line 10 and the effluent line 17 is made as short as possible, and 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) A polyacyl compound can be synthesized continuously at high speed from a carboxylic acid anhydride and a polyheterohydride.
(2) A polyacyl compound can be selectively synthesized by adjusting the acylation number.
(3) A synthesis process of a polyacyl compound without using a catalyst and an organic solvent can be realized.
(4) Therefore, it is possible to provide a highly safe biocompatible polyacyl compound composition having no catalyst and organic solvent remaining and not harmful to the living body.
(5) When the product does not dissolve in water, water is injected into the discharged oil-water dispersion aqueous solution to separate the oil and water into two layers while washing, and a high-purity product can be easily obtained. Can be recovered.
(6) As a new mass production process of a polyacyl compound having biocompatibility useful as a fragrance, a pharmaceutical, and a food, a new production technique that can replace an existing production process can be provided.

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

Examples 1-4
In this example, the synthesis conditions were 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 the substrate), and a mixed solution of acetic anhydride / substrate / acetic acid (molar ratio: 1.1 / 1 / 0.5 to 1) 0.5 ml / min was pumped. (Aqueous solution concentration after mixing: 0.26 to 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)).

  Table 1 shows the results of polyacylation in the case where the α-position skeleton is the same diol. In the case of catechol (1), the molar ratio is acetic anhydride / 1 / acetic acid = 1.1 / 1 / 0.5, the temperature is 225 ° C., the conversion is 85%, and the monoacetate (1a) is obtained with the selectivity of 65%. It was. Further, the molar ratio was acetic anhydride / 1 / acetic acid = 2.2 / 1 / 1.0, the temperature was 225 ° C., the conversion rate was 100%, and diacetate (1b) was obtained with the selectivity of 93% (Table 1, Examples 1, 2). On the other hand, in the case of ethylene glycol (2), the molar ratio is acetic anhydride / 2 / acetic acid = 1.1 / 1 / 0.5, the temperature is 200 ° C., the conversion is 36%, and the diacetate (2b) is the selectivity 100%. Monoacetate (2a) was not obtained. Further, the molar ratio was acetic anhydride / 2 / acetic acid = 2.2 / 1 / 1.0, and a conversion rate of 99% and diacetate (2b) were obtained at a selectivity of 100% at a temperature of 200 ° C. (Table 1, Examples 3 and 4).

  The obtained 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 benzyl acetate containing no acetic acid is added to the lower oil layer. An aqueous acetic acid solution was obtained in the aqueous phase (confirmed by GC). This means that when the product does not dissolve in water, it is possible to separate the polyacyl compound and the acetic acid aqueous solution by changing water into two layers by further injecting water into the aqueous oil-dispersed 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 5-10
In this example, the synthesis conditions were constant under the conditions of no catalyst, a predetermined temperature, a pressure of 5 MPa, and a residence time of 9.9 seconds, and diols having different α-position skeletons were examined. 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 the substrate), and 0.5 ml / min of a mixed solution of acetic anhydride / substrate / acetic acid (molar ratio: 1.1 / 1/1 to 2) was pumped ( Aqueous solution concentration after mixing: 0.26 to 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)).

  Table 2 shows the results of polyacylation in the case of diol and glycerin having different skeletons at the α-position. In the case of 1,3 butanediol (3) where the α-position of the alcohol has primary and secondary at the same time, the molar ratio is acetic anhydride / 3 = 1.1 / 1, the temperature is 225 ° C., the conversion is 94%, Monoacetate (3a) was obtained with a selectivity of 72%. Further, the molar ratio was acetic anhydride / 3 = 2.2 / 1, the temperature was 225 ° C., the conversion was 99.9%, and the diacetate (3b) was obtained with a selectivity of 99.9% (Table 2, Implementation). Examples 5, 6). On the other hand, in the case of 1-methyl-1,3-butanediol (4) in which the α-position of the alcohol has primary and tertiary at the same time, the molar ratio is acetic anhydride / 4 = 1.1 / 1, and the temperature is 200 ° C. The conversion was 99.8% and monoacetate (4a) was obtained with a selectivity of 86% (Table 2, Example 7). Further, the molar ratio was acetic anhydride / 4 = 2.2 / 1, the temperature was 200 ° C., the conversion was 99%, and diacetate (4b) was obtained with the selectivity of 64% (Table 2, Example 8). Here, when the molar ratio was acetic anhydride / 4 = 2.2 / 1 and the temperature was 225 ° C., the conversion was 94% and the diacetate (4b) was improved to 74% (Table 2, Example 9). ). Furthermore, a molar ratio of acetic anhydride / 4 = 5.1 / 1, a temperature of 200 ° C., a conversion of 99%, and diacetate (4b) were selectively obtained with a selectivity of 99.7% (Table 2, implementation). Example 8).

Examples 11-14
In this example, glycerin (5), which is a triol having both primary and secondary skeletons with different α-position skeletons under constant conditions of no catalyst, predetermined temperature, pressure of 5 MPa, and residence time of 9.9 seconds. Was examined. 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 the substrate), and 0.5 ml / min of a mixed solution of acetic anhydride / substrate / acetic acid (molar ratio: 1.1 / 1/1 to 3) was fed by a pump ( Aqueous solution concentration after mixing: 0.26 to 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, the molar ratio was acetic anhydride / 5 / acetic acid = 1.1 / 1/1, the temperature was 200 ° C., the conversion was 91%, and the monoacetate (5a) was obtained with the selectivity of 59%, and the temperature was 225 ° C. A conversion of 93% and monoacetate (5a) were obtained with a selectivity of 52% (Table 2, Example 11, Example 12). Further, a molar ratio of acetic anhydride / 5 / acetic acid = 2.2 / 1/2, a temperature of 225 ° C., a conversion of 98%, and a diacetate (5b) with a selectivity of 25% were obtained (Table 2, Examples). 13). Furthermore, the molar ratio was acetic anhydride / 5 / acetic acid = 3.3 / 1/3, the temperature was 225 ° C., the conversion rate was 100%, and the triacetate (5c) was obtained with the selectivity of 96% (Table 2, Example 14). ).

  From the above examples, it was revealed that polyacyl compounds can be synthesized in high yield without catalyst using high-temperature and high-pressure water as a reaction solvent. After acylation, water is injected into the recovered aqueous solution, followed by decantation. After separation into an oil / water bilayer solution, an oil layer containing a polyacyl compound is separated and recovered, while acetic acid and water are azeotroped from the aqueous layer. It became clear that a simple continuous separation method of separating and recovering by distillation was also feasible.

  As described in detail above, the present invention provides a method for synthesizing a polyacyl compound without using an organic solvent from a carboxylic acid anhydride and a polyhetero hydride, using a high-temperature and high-pressure fluid as a reaction solvent, and the temperature and carboxylic anhydride. A method for selectively synthesizing a polyacyl compound by acylating in the order of primary, secondary, and tertiary by adjusting the amount of acid to adjust the number of acylation, an apparatus thereof, and a reaction composition thereof. In the conventional method, the synthesis of polyacyl compounds from polyheterohydrides and carboxylic acid anhydrides was carried out by adding a catalyst to an organic solvent, reacting for several hours, and acylating all, so the acylation number could not be adjusted. However, in the present invention, by using a subcritical fluid or a supercritical fluid, a polyacyl compound can be selectively selectively continuously at high speed without using a catalyst and without using an organic solvent. It is possible to synthesize. This brings about the merit that polyacyl compounds having biocompatibility useful as fragrances, pharmaceuticals, and foods can be continuously produced in large quantities in a short time. After acylation, water is injected into the recovered aqueous solution, followed by decantation. After separation into an oil / water bilayer solution, an oil layer containing a polyacyl compound is separated and recovered, while acetic acid and water are azeotroped from the aqueous layer. By simple continuous separation of reaction system components separated and recovered by distillation, it is possible to separate glacial acetic acid and water and recycle the water. 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 existing production processes as a new mass production process of polyacyl compounds having biocompatibility useful as, for example, perfumes, pharmaceuticals, and foods.

The acylation of polyheterohydride using 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.

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 (10)

  A polyacyl compound composition characterized in that a reaction composition synthesized by a reaction of a carboxylic anhydride and a polyheterohydride has no residual catalyst and organic solvent and has biocompatibility.   A process for synthesizing a polyacyl compound from a carboxylic anhydride and a polyheterohydride, 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 method, a polyacyl compound is selectively synthesized from a carboxylic anhydride and a polyheterohydride by a one-step synthesis reaction without using a catalyst.   The method according to claim 2 or 3, wherein the heteroatom or substituted heteroatom in the polyheterohydride is oxygen (O), sulfur (S), hydrogen nitride (NH), or alkyl-substituted nitrogen (NR ').   By adjusting the temperature and the amount of carboxylic anhydride corresponding to the number of substitutions at the α-position adjacent to the heterohydrogen group in the substrate, there is no substitution (primary), monosubstitution (secondary), disubstitution (tertiary) The method according to claim 2 or 3, wherein a polyacyl compound is selectively synthesized by adjusting the number of acylation while acylating in the order of).   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 apparatus for synthesizing a polyacyl compound 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 a polyacyl compound is separated and recovered, while an aqueous layer Is a simple continuous separation method of reaction system components characterized in that acetic acid and water are separated and recovered by azeotropic distillation.

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