JP2007297338A - N-acyl compound, and method and device for producing the same - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for synthesizing N-acyl compound from a carboxylic anhydride and a heterohydride, in the absence of a catalyst, in a short time, continuously, at a high yield/high selectivity, and to provide reaction products thereby. <P>SOLUTION: The production method of N-acyl compound comprises synthesizing N-acyl compound from a carboxylic anhydride and a heterohydride, at a high yield, with high selectivity, rapidly/continuously, by using, as the reaction solvent, a normal temperature fluid in the case of exothermic reaction, or a 100-400°C 0.1-40 MPa subcritical fluid or critical fluid in the case of endothermic reaction, introducing, in the absence of catalyst, a substrate and the reaction solvent to a normal-temperature high-pressure flow reactor in the case of exothermic reaction, or a high temperature high pressure flow reactor in the case of endothermic reaction, and changing several conditions of temperature and carboxylic anhydride amount. And reaction products thereby and devices therefor are provided. <P>COPYRIGHT: (C)2008,JPO&INPIT

Description

  The present invention relates to an N-acyl compound, a process for producing the same, and an apparatus thereof. More specifically, N-acyl compound is a non-catalytic and one-step process using water at normal temperature, high temperature and high pressure, or a mixed solvent thereof as a reaction solvent. The present invention relates to a method for producing an acyl compound. In the case of an exothermic reaction, normal temperature water or acetic acid and a mixed solvent thereof are used as a reaction solvent, and in the case of an endothermic reaction, water or acetic acid at a temperature of 100 to 400 ° C. and a pressure of 0.1 to 40 MPa, The present invention provides a method for continuously synthesizing an N-acyl compound from a carboxylic anhydride and a heterohydride in a single step and in a short time without adding a catalyst, using the mixed solvent as a reaction solvent, and a reaction composition thereof. Here, the hetero atom in the hetero hydride includes nitrogen and corresponds to an amine or aniline derivative.

  The N-acyl compound is useful in the field of fragrances, pharmaceuticals, foods and the like because it improves and improves the functionality of raw materials and substrates, and further adds added value. Normally, when synthesizing N-acyl compounds, the conventional method requires an acid / base catalyst in addition to the aprotic organic solvent. When used in foods and pharmaceuticals, the remaining organic solvent and catalyst are removed. 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 of synthesizing an N-acyl compound from a heterohydride of a carboxylic anhydride and an amine or aniline derivative without using a catalyst and using only water, and a reaction composition thereof. The present invention can be applied not only to pharmaceuticals and foods but also to chemical synthesis, and it is possible to produce and provide N-acyl compounds efficiently and in a short time.

Conventionally, various methods for synthesizing N-acyl compounds from carboxylic anhydrides and heterohydrides, amines or aniline derivatives have been reported (for example, see Non-Patent Document 1). In the case of N-acylation, a method applicable to O-acylation of alcohol is often applicable to N-acylation, and therefore there are few documents compared to O-acylation. According to prior art documents, sulfuric acid as a strong acid, TsOH (Non-patent Document 2), metal chlorides ZnCl ₂ (Non-patent Document 3), CoCl ₃ (Non-patent Document 3) as a catalyst in a solvent-free or aprotic organic solvent. Non-patent document 4), Me ₃ SiCl (non-patent document 5), bases Bu ₃ P (non-patent document 6), NaOAc (non-patent document 7), pyridine (non-patent document 8) and the like have been used. . In addition, the discovery of DMAP that activates an acyl group through the formation of a stable acyl intermediate was regarded as an innovative technique (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), Sc (NTf) ₃ (Non-Patent Document 14), HNTf ₂ (Patent Documents 1 and 2) Was shown to give the N-acyl compound in high yield. 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). These catalysts are reported to yield N-acyl compounds in yields of 90% or more from primary, secondary amines or aniline derivatives (FIG. 1).

  Here, in the above prior art documents, an organic solvent is indispensable for N-acylation in addition to a catalyst such as an organic base, a Lewis acid, and a solid acid. In addition, N-acylation is optimally performed at room temperature because impurities are generated under high temperature conditions and the selectivity is lowered, and high temperature conditions are not suitable (Patent Documents 1 and 2). . On the other hand, regarding the possibility of water as a solvent in N-acylation, a method of adding an acylating agent to a crude product and acylating under anhydrous conditions is common, and water is N-acylated. (Patent Document 4). In a certain patent document, water is listed as a solvent, but it is not actually used (see Patent Documents 1 and 2).

However, 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 there is an example that 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). Therefore, from the above prior literature, the effectiveness of water as a solvent for N-acylation has not been clear or implemented so far.

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). However, a method of N-acylation from an amine / aniline derivative in an organic solvent or room temperature water at a yield of 66% or more using N-methoxyacetamide as a catalyst has been reported. When a non-Lewis acid catalyst is used, Was first shown to be usable as a solvent. However, N-methoxyacetamide as an acylating agent has a problem that it is very expensive compared to carboxylic anhydride (Non-patent Document 17).

  The post-treatment after the reaction is performed by adding a neutralizing agent to the reaction mixture for neutralization in a normal catalyst / organic solvent after N-acylation, adding an extraction solvent and water or a saturated saline solution, and separating the solution. The layer is then subjected to a process of drying, solvent removal, distillation or rectification to obtain the desired product, while in the water layer, in addition to water, catalyst, organic solvent, acetic acid, substrate, product, by-product Complex mixtures of materials and minerals. 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). As in the case of acylation in non-catalyzed high-temperature and high-pressure water, if the water layer does not contain catalyst or organic solvent but contains only water, acetic acid and product, the product is separated by decantation. Then, it can be separated into water and glacial acetic acid by performing azeotropic distillation to which a substance that forms an azeotropic mixture is added to the aqueous layer (Patent Document 5). This means that the water can be regenerated and is a process of reducing the environment as compared with 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.M. G. Wuts, Protective Groups in Organic Synthesis, 3rd ed. , Wiley, New York, 1999, p150 A. C. Cope, E .; C. Herrick, Org. Syn. Coll. , Vol. 4,1963,304 R. H. Baker, E .; C. Herrick, Org. Syn. Coll. , Vol. 3,1955,141 S. Ahmad, J. et al. Iqbal, Chem. Commun. , 1987, 114. N. C. Braus, R.M. P. Sharma, J .; N. Baruah, Tetrahedron Lett. , 1983, 24, 1189; Org. Chem. , 1987, 52, 5034 E. Vedejs, N.M. S. Bannet, L.M. M.M. Conn, S.M. T. T. et al. Diver, J .; Org. Chem. 1993, 58, 7286 The Miner Laboratories, Org. Syn. Coll. Vol. 1,1941,285 Joseph B. Lambert, Gen Tai Wang, Rodney B .; Finzel, and Douglas H.M. Teramura, J.M. Am. Chem. Soc. , 1987, 109, 7838. G. Hofle, W.M. Steglich, H.M. Vorbruggen. , Angrew. Chem. Int. Ed. 1978, 17, 569. b) A. Hassner, L .; R. Krepski, V.M. Alexian, Tetrahedron, 1978, 34, 2069 P. A. Procopiu, S.M. P. D. Baugh, S.M. S. Flack, G.M. G. A. Inglis, J. et al. Org. , Chem. 1998, 63, 2342 a) K.K. Ishihara, M .; Kubota, H .; Kurihara, H .; Yamamoto, J. et al. Org. Chem. , 1996, 61, 4560. b) K.K. Ishihara, M .; Kubota, H .; Kurihara, H .; Yamamoto, J. et al. Am. Chem. Soc. 1995, 117, 4413. K. K. Chauhan, C.I. G. Frost, I.D. Love, D.D. Waite, Synlett, 1999, 1743 J. et al. Otera, A .; Orita, C.I. Tanahashi, A.A. Kakuta, Angrew. Chem. Int. Ed. 2000, 39, 2877 K. Ishihara, M .; Kubota, Synlett, 1996, 265 CT Chen, JH. Kuo, C-H. Li, N .; B. Barhate, SW. Hon, TW. Li, SD. Chao, CC. Liu, YC. Li, I-H. Chang, JS. Lin, CJ. Liu and YC. Chou, Org. Lett. , 2001, 3, 3729 S. Kobayashi, S .; Nagayama, T .; Busimama, J .; Am. Chem. Soc. 1998, 120, 8287 Y. Kikugawa, K. et al. Mitsui, T .; Sakamoto, M .; Kawase, and H.K. Tamiya, Tetrahedron Lett, 1990, 31, 2, 243

  Thus, in the conventional method, in the case of N-acylation, a catalyst and an organic solvent are necessary. Therefore, in the separation operation after the reaction, removal of the catalyst, the organic solvent and the carboxylic acid is necessary in terms of product quality. The water layer after the separation operation tends to be waste, and causes 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 advanced separation is comparable to that of the synthesis operation, and preferably no catalyst and organic solvent are used. In view of the above, in this technical field, a continuous synthesis of N-acyl compounds that can be easily separated and easily separated by a simple, low-cost, environmentally-reduced synthesis process and that does not have any catalyst or organic solvent remaining. There has been a strong demand for a synthesis method that enables this.

  Under such circumstances, in view of the prior art, the present inventors are able to continuously synthesize the N-acyl 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 a synthesis method, as a reaction solvent using high-temperature and high-pressure water, subcritical water or supercritical water, N- The inventors have found that acyl compounds can be synthesized, and have completed the present invention. An object of the present invention is to provide a method of continuously synthesizing an N-acyl compound from a carboxylic anhydride and a heterohydride under a reaction condition in a short time without using a catalyst, and a reaction composition thereof. is there.

The present invention for solving the above-described problems comprises the following technical means.
(1) A N-acyl compound composition, which is a reaction composition of a carboxylic anhydride and a heterohydride, and has no catalyst and organic solvent remaining.
(2) A method for synthesizing an N-acyl compound from a carboxylic anhydride and a heterohydride, in the case of an exothermic reaction, a normal temperature fluid, and in the case of an endothermic reaction, a subcritical fluid or supercritical fluid in a high temperature and high pressure state. A method for producing an N-acyl compound, wherein a fluid is used as a reaction solvent, and an N-acyl compound is selectively synthesized from a carboxylic anhydride and a heterohydride by a one-step synthesis reaction without using a catalyst. .
(3) The method for producing an N-acyl compound according to (2), wherein subcritical or supercritical water in a high temperature and high pressure state is used as a reaction solvent.
(4) The method according to (2) above, wherein the heteroatom or substituted heteroatom in the heterohydride is hydrogen nitride (NH) or alkyl-substituted nitrogen (NR ′).
(5) The N-acyl compound is selectively synthesized by adjusting the temperature or the amount of carboxylic anhydride with respect to the primary, secondary, or tertiary skeleton adjacent to the reaction point of the substrate, 2) The method described.
(6) The method according to (2) above, 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.
(7) The method according to (2) above, wherein water, acetic acid, another inorganic solvent, an organic solvent, or a mixed solvent of an inorganic solvent and an organic solvent is used as the normal temperature fluid, subcritical fluid or supercritical fluid.
(8) The method according to (2) above, 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.
(9) In the case of an exothermic reaction, a substrate and a reaction solvent are introduced into a flow-type room temperature high pressure apparatus, and the reaction time is changed in the range of 1 to 60 seconds, and the synthesis reaction is performed. Method.
(10) A water feed pump for feeding water, a high-temperature high-pressure flow cell, a reactant feed pump for feeding a substrate, a furnace body, a reactant introduction pipe for introducing the reactant into the furnace body, and a discharge for discharging the reaction solution An N-acyl compound synthesizing apparatus comprising a liquid line, a cooling flange, and a back pressure valve for setting a pressure.
(11) In the case of an endothermic reaction, the N-acyl compound synthesis device according to (10) above, wherein a water heating coil is provided.
(12) In the method described in (2) above, after N-acylation, water is poured into the recovered aqueous solution and decanted, and after separation into an oil / water bilayer solution, the oil layer containing the N-acyl compound is separated. A simple continuous separation method that separates and recovers acetic acid and water from the aqueous layer by azeotropic distillation.

Next, the present invention will be described in more detail.
According to the present invention, an N-acyl compound is converted from a carboxylic acid anhydride of Chemical Formula 1 and a heterohydride of Chemical Formula 2 as shown in Chemical Formula 3 into a one-step reaction process without adding a catalyst and under short reaction conditions. Thus, the synthesis is performed selectively and continuously. In the present invention, a normal temperature fluid is used as the reaction solvent in the case of an exothermic reaction, and a subcritical fluid or a supercritical fluid at a temperature of 100 to 400 ° C. and a pressure of 0.1 to 40 MPa is used in the case of an endothermic reaction. In the case of exothermic reaction, water is used, and in the case of endothermic reaction, subcritical water is used.

As the reaction conditions, preferably, in the case of an exothermic reaction, normal temperature and pressure and the reaction time are adjusted to about 1 second, and in the case of an endothermic reaction, the temperature is 200 to 250 ° C., the pressure is 5 MPa, and the reaction time is 3 to 60 seconds. The range is preferably adjusted to about 10 seconds. In the formula (1), R is an alkyl group and a substituent containing a hetero atom other than an alkyl group. In the formula (2), R 1, R 2 and R 3 are substituents containing a hetero atom other than an alkyl group and an alkyl group. And Q is carbon, a heteroatom other than carbon, or a substituted heteroatom. Q ₁ is a heteroatom or a substituted heteroatom, specifically, hydrogen nitride (NH) or alkyl-substituted nitrogen (NR ′).

  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 room temperature high pressure apparatus or a high temperature high pressure reaction vessel, and a continuous flow type room temperature high pressure apparatus or a flow type high temperature high pressure reaction apparatus can be used. There are no particular restrictions on the type of these reactors.

  In the method of the present invention, a normal temperature fluid, a subcritical fluid in a high temperature and high pressure state, or a supercritical fluid is used as a reaction solvent. Specifically, subcritical carbon dioxide (normal temperature or higher, 0.1 MPa or higher), Critical water (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), these in the same state And a normal temperature water or subcritical water (200-250 ° C., 5 MPa or more) is preferably used. As a reaction solvent, an organic solvent or an inorganic solvent other than the above can be contained in any proportion, and specifically, a reaction that includes acetone, acetonitrile, tetrahydrofuran, or the like as an organic solvent, and acetic acid, ammonia, or the like as an inorganic solvent. A solution can be substituted.

  In the present invention, by adjusting the composition of the reaction solvent of the normal temperature fluid, subcritical fluid, and supercritical fluid, temperature and pressure conditions, the type and amount of the substrate used, and the reaction time, the reaction can be efficiently performed in a short time. The product can be synthesized. In the present invention, for example, a substrate and a reaction solvent are introduced into a flow-type room temperature high-pressure apparatus, and their reaction time is changed within a range of 1 to 60 seconds, or they are introduced into a flow-type high-temperature high-pressure apparatus. By changing the reaction time in the range of 3 to 60 seconds, a predetermined reaction product 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, synthesis of an N-acyl compound from a carboxylic acid anhydride and a heterohydride, which has been conventionally performed in the presence of a catalyst, can be carried out continuously at high speed and without a catalyst. Processes that require a long time can be made more efficient. Further, in the method of the present invention, since a conventionally used catalyst is not used at all, there is no need for post-treatment / disposal such as neutralization treatment and detoxification treatment of the solution after the reaction, and environmental load reduction can be achieved. . Further, after the reaction, only a stationary separation operation such as decantation is performed, so that there is no need to separate and recover the catalyst and the organic solvent, and the product separation becomes easy.

  According to the present invention, no catalyst is added, and in a short time of about 10 seconds, when the substrate is a primary amine / aniline derivative, the selectivity is 100%, the yield is 99%, and the secondary amine / aniline derivative is selected. In the case of a tertiary amine / aniline derivative, the selectivity is 100% or more and the yield is 85% or more. In the case of the aniline derivative, the selectivity is 100% or more and the yield is 85% or more. The corresponding N-acyl compound can be synthesized. The synthesis method of the present invention is useful as one that enables efficient, large-scale, high-speed, continuous production of N-acyl compounds that can be used in fragrances, pharmaceuticals, and foods.

  Conventionally, an example of carrying out acylation using a lipase or a catalyst using a subcritical fluid such as carbon dioxide or a supercritical fluid has been reported. However, there is no example demonstrating that an N-acyl compound can be synthesized in a high yield from a carboxylic acid anhydride and a heterohydride in a non-catalytic room temperature water or subcritical water process. -The method for synthesizing acyl compounds has been demonstrated for the first time by the present inventors. Moreover, the N-acyl compounds synthesized from carboxylic acid anhydrides and heterohydrides by conventional methods have been problematic in terms of remaining catalyst and organic solvent. However, in the present invention, they are synthesized from carboxylic acid anhydrides and heterohydrides. The reaction composition thus obtained has no remaining catalyst and organic solvent, and the N-acyl compound composition of the present invention has advantages not found in conventional products.

  In the present invention, in order to realize the synthesis reaction of carboxylic anhydride and heterohydride under non-catalytic conditions, for example, a solution in which a substrate is previously dissolved in a solvent is fed, and a room temperature fluid, a subcritical fluid, a supercritical fluid It is also possible to use a flow-type high-temperature high-pressure infrared spectroscopic in-situ measuring device (FIG. 5) for observing the progress of the reaction 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, an apparatus equipped with this windowless high-temperature and high-pressure flow cell was used in Examples described later.

  Here, the windowless high-temperature and high-pressure flow cell main body (FIG. 6) is made so that, for example, a commercially available SUS316 cloth 1 is threaded and fixed to a temperature sensor sheath (12 in FIG. 7) described below. The temperature sensor is adjusted so as to indicate the cell temperature without measuring the temperature of the furnace atmosphere, and is fixed 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. 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 shown in Fig. 5, the infrared spectroscopy cannot be measured, but subcritical / supercritical fluid contact synthesis with variable temperature, pressure and flow rate. It can be used as a reactor. FIG. 8 shows a flow-type room temperature and high pressure reaction apparatus in the case of an exothermic reaction, which is a reaction apparatus main body. Also in this case, it can be used as a room temperature fluid contact synthesis reaction apparatus in which the temperature, pressure and flow rate around room temperature are variable. In these cases, the reaction was observed by collecting the aqueous solution after discharge, quantifying it from a calibration curve using a pure product by GC-FID, and performing qualitative analysis by GC / MS.

  Hereinafter, with reference to FIG. 7, water is fed from the water feed pump 5, and after passing through the cooling flange 8, is 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, is sent to the furnace body 13, passes through the coiled reactant introduction pipe 10, and is fixed to the temperature sensor sheath 12. Introduced into the high-temperature and high-pressure flow cell 14. 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 effluent containing the reactants and products, rapid heating is performed, and the piping of the reactant introduction line 10 and the effluent line 17 is made as short as possible for water heating. It is desirable to make the coil 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.

  On the other hand, referring to FIG. 8, which is a room temperature reaction apparatus, a reaction in which a carboxylic acid anhydride and an amine or aniline derivative are fed from a reactant feed pump 40 and a substrate feed pump 41, respectively, and a temperature sensor 50 is mounted. The tee 43 mixes and reacts, and the reaction solution passes through the pipe 44. Thereafter, the reaction solution is mixed and cooled with the water fed from the water feed pump 42 by the mixing tee 45 equipped with the temperature sensor 51 in order to suppress the generated reaction heat, and the discharge pipe 46 and the back pressure valve 48 are set. After passing, it is recovered in the recovery container 49. In this case, the reaction tee 43, the pipe 44, the mixing tee 45, and the discharge pipe 46 can be immersed in a cooler in order to suppress the generated reaction heat. In addition, in order to suppress reaction heat generated without sending water from the total water pump 42, the reaction tee 43, the pipe 44, the mixing tee 45, and the discharge pipe 46 are immersed in a cooler, and solvent-free conditions are satisfied. It is also possible to make it react. 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 N-acyl compound can be synthesized continuously from a carboxylic acid anhydride and a heterohydride in one step at a high speed.
(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 N-acyl compound composition that is free from residual catalyst and organic solvent and is not harmful to the living body.
(4) 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, making it easy to produce a high-purity product. Can be recovered.
(5) According to the present invention, as a new mass production process of N-acyl compounds useful in the fields of fragrances, pharmaceuticals and foods, 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.

First, after showing an implementation method, a concrete Example is shown.
(1) Method using a flow-type high-temperature and high-pressure reactor (method SF in Tables 1 to 3)
In this example, using the flow-type high-temperature and high-pressure reactor shown in FIG. 7, the synthesis conditions were as follows: no catalyst, temperature 50 to 200 ° C., pressure 5 MPa, residence time 9.9 seconds. The main body (main part) of the flow-type high-temperature and high-pressure reactor shown in FIG. 7 is set in the flow-type high-temperature and high-pressure fluid in situ infrared spectrometer shown in FIG. None The connection hole of the cell (tee 1) with the piping coil 9 is closed at the end, the flow path to the piping coil 9 is closed by the pump 5, and pure water is sent to the tee 18 outside the furnace body at a flow rate of 5.0 ml / min. Liquid. Thereafter, toluene was added as an internal standard (5 mol% of the substrate), and a carboxylic acid anhydride / amine or aniline derivative (molar ratio: 1.1 / 1) mixed solution 0.5 ml / min was pumped (mixed) Later 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 of 2 minutes)). In addition, quantitative analysis and qualitative analysis in the case where there is a commercially available reagent are GC-FID (GC6890 manufactured by Agilent, column DB-WAX, inlet temperature 230 ° C., split ratio 5.61, initial column temperature 50 using toluene as an internal standard. C. (retention time 0.5 minutes), temperature increase rate 20 ° C./minute, final column temperature 230 ° C. (retention time 3 minutes)).

(2) Method using a flow-type room temperature high pressure reactor (methods AF1 and AF2 in Tables 1 to 3)
On the other hand, when the reaction is an exothermic reaction and it is difficult to synthesize with a flow-type high-temperature and high-pressure reactor, that is, when synthesis is difficult with the flow-type high-temperature and high-pressure reactor shown in FIG. N-acylation was performed. The synthesis conditions were as follows: no catalyst, pressure 0.1 MPa, residence time 1.1 seconds constant. The amine or aniline derivative added with carboxylic acid anhydride and toluene as internal standards (5 mol% of the substrate) is fed to the main body of the flow-type room temperature high pressure reactor shown in FIG. 8 respectively, and pure water is supplied at a flow rate of 5.0 ml. The solution was fed at / min. 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 reaction tee to the back pressure valve outlet was the reaction volume, the reaction time was 1.1 seconds.

  1 ml of acetone was added to 1 ml of the collected aqueous solution, 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 minutes), a temperature rising rate of 10 ° C./min, and a final column temperature of 250 ° C. (holding time of 2 minutes)), and the obtained mass spectrum was confirmed with a Willy database with a coincidence of 90% or more. In addition, quantitative analysis and qualitative analysis in the case where there is a commercially available reagent are GC-FID (GC6890 manufactured by Agilent, column DB-WAX, inlet temperature 230 ° C., split ratio 5.61, initial column temperature 50 using toluene as an internal standard. C. (retention time 0.5 minutes), temperature increase rate 20 ° C./minute, final column temperature 230 ° C. (retention time 3 minutes)). When the reaction is completed and the solid is deposited and clogged when discharged from the back pressure valve, the case where acetic acid is added to the carboxylic acid anhydride, the case where acetic acid is added to the method AF1, the amine / aniline derivative, Method AF2.

(3) Simplified batch method (Method B in Tables 1 to 3)
Further, in order to confirm the solubility and the reaction, carboxylic anhydride and an amine or aniline derivative were added dropwise to a 30 ml vial, and then toluene was added as an internal standard (5 mol% of the substrate). Here, when it was highly viscous or solid and difficult to dissolve, an appropriate amount of acetic acid was added, and the mixture was shaken with warm water to confirm the solubility in acetic acid. Furthermore, 1 ml of acetone was added to 1 ml of the aqueous solution collected from this mixed 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. (holding time 2 minutes), heating rate 10 ° C./min, final column temperature 250 ° C. (holding time 2 minutes)), and the obtained mass spectrum was confirmed by the Willy database with a concordance of 90% or higher. . In addition, quantitative analysis and qualitative analysis in the case where there are 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)).

  In addition, when the obtained aqueous product solution is clouded 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. Acetic acid is added to the lower (upper) oil layer. An acetic acid aqueous solution was obtained from the upper (lower) aqueous phase of the N-acyl compound containing no N2 (confirmed by GC). This means that when the product does not dissolve in water, it is possible to separate the N-acyl compound and the aqueous acetic acid solution by changing water into two layers by further injecting water into the aqueous oil-dispersed aqueous solution after completion of the reaction. it can. 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.

  Table 1 shows the results of N-acylation of amines and aniline derivatives. Table 2 shows the results of N-acylation of amines and aniline derivatives. Table 3 shows the results of N-acylation in OH group-containing amines and aniline derivatives.

(Examples 1 and 2)
When piperidine 1 and 1.1 molar equivalent of acetic anhydride were used as a substrate and N-acylation was carried out by Method AF1, N-acetyl isomer 1a was obtained with a conversion of 99.8% and a selectivity of 100%. However, when the method SF was carried out at 200 ° C. and 5 MPa, the conversion rate was extremely reduced to 18%.

(Example 3)
When N-acylation was performed by Method AF1 using methylpiperidine 2 and 1.1 molar equivalent of acetic anhydride as a substrate, N-acetyl isomer 2a was obtained with a conversion rate of 100% and a selectivity of 100%.

(Examples 4, 5, and 6)
When 2,6-dimethylpiperidine 3 and 1.1 molar equivalent of acetic anhydride was used as a substrate and N-acylation was performed by Method AF1, the N-acetyl form 3a was reduced to a conversion rate of 3%. Therefore, when the method SF was carried out at a temperature of 50 ° C., a pressure of 5 MPa, and a residence time of 9.9 seconds, a conversion rate of 47% was obtained, and further, 100 ° C., a pressure of 5 MPa, and a residence time of 9.9 seconds were carried out. However, a conversion rate of 85% was obtained. In all cases, the selectivity was 100%.

(Examples 7 and 8)
When N-acylation was performed by Method AF1 using aniline 4 and 1.1 molar equivalent of acetic anhydride as a substrate, N-acetyl derivative 4a was obtained with a conversion of 98% and a selectivity of 100%. Further, when the method AF2 using a solution obtained by adding acetic acid to aniline 4 was used, the N-acetyl derivative 4a was obtained with a conversion rate of 97% and a selectivity of 100%, and almost the same result as in the method AF1 was obtained. It was.

(Examples 9 and 10)
When 2,6-dimethylaniline 5 and 1.1 molar equivalents of acetic anhydride are used as a substrate and N-acylation is carried out by Method AF1, N-acetyl compound 5a is obtained with a conversion of 98% and a selectivity of 100%. It was. Further, when the method AF2 using a solution obtained by adding acetic acid to 2,6-dimethylaniline 5 was carried out, an N-acetyl form 5a was obtained with a conversion rate of 84% and a selectivity of 96%. However, both the conversion rate and the selectivity decreased somewhat.

(Example 11)
When sec-butylamine 6 and 1.1 molar equivalent of acetic anhydride were used as a substrate and N-acylation was performed by Method AF1, N-acetyl compound 6a was obtained with a conversion rate of 100% and a selectivity of 99%.

(Example 12)
When N-acylation was performed with Method AF1 using tert-butylamine 7 and 1.1 molar equivalent of acetic anhydride as a substrate, the conversion was lower than that of sec-butylamine 6 and the conversion was 88%. N-acetyl 7a was obtained at a rate of 100%.

(Examples 13-18)
When N-acylation was carried out by Method AF1 using anthranilic acid 8 and 1.1 molar equivalent of acetic anhydride as a substrate, there was no reaction. Therefore, when the method SF was carried out at a temperature of 150 ° C., a pressure of 5 MPa, and a residence time of 9.9 seconds, an N-acetyl compound 8a was obtained with a conversion rate of 1% and a selectivity of 71%, a temperature of 50 ° C., a pressure of 5 MPa, When carried out at a residence time of 9.9 seconds, the conversion was 82% and the selectivity was 91%, and further at a temperature of 75 ° C., a pressure of 5 MPa and a residence time of 9.9 seconds, the conversion was 96% and the selectivity was 99. % N-acetyl compound 8a was obtained. In addition, when the method B was carried out with acetic anhydride / acetic acid = 1.1 / 15 molar equivalent, the conversion was as low as 53%, but when carried out with only acetic anhydride, the conversion was 91% and the selectivity was 80%. The result was obtained.

(Examples 19 and 20)
When caprolactam 9 and 1.1 molar equivalent of acetic anhydride were used as substrates, N-acylation was carried out by method SF at a temperature of 200 ° C., a pressure of 5 MPa, and a residence time of 9.9 seconds. The N-acetyl compound 9a was obtained at 100%, and the N-acetyl compound 9a was obtained at a conversion rate of 85% and a selectivity of 100% when carried out at a temperature of 225 ° C., a pressure of 5 MPa, and a residence time of 9.9 seconds.

(Example 21)
When N-acylation was carried out by Method AF1 using ethylenediamine 10 and 2.2 molar equivalents of acetic anhydride as a substrate, N, N-diacetyl compound 10a was obtained with a conversion of 99% and a selectivity of 100%.

(Examples 22 and 23)
When N-acylation was performed by Method AF1 using 2-aminoethanol 11 and 1.1 molar equivalent of acetic anhydride as a substrate, N-acetyl compound 11a was obtained at a conversion rate of 100% and a selectivity of 100%. . Here, when the method SF was carried out at a temperature of 200 ° C., a pressure of 5 MPa, and a residence time of 9.9 seconds, an N-acetyl compound 11a was obtained with a conversion rate of 100% and a selectivity of 35%.

(Examples 24 and 25)
When 3-aminoethanol 12 and 1.1 molar equivalent of acetic anhydride was used as a substrate and the method AF1 was used, N-acetyl compound 12a was obtained with a conversion rate of 1% and a selectivity of 71%. Here, when the method SF was carried out at a temperature of 200 ° C., a pressure of 5 MPa, and a residence time of 9.9 seconds, an N-acetyl compound 12a was obtained with a conversion rate of 100% and a selectivity of 35%.

(Examples 26-30)
When 4-aminophenol 13 and 1.1 molar equivalent of acetic anhydride were used as a substrate and the method AF1 was used, N-acetyl compound 13a was obtained with a conversion of 7% and a selectivity of 2%. Here, when the method SF was carried out at a temperature of 100 ° C., a pressure of 5 MPa, and a residence time of 9.9 seconds, an N-acetyl compound 13a was obtained with a conversion rate of 9% and a selectivity of 14%, and a temperature of 150 ° C. and a pressure of 5 MPa. When the retention time was 9.9 seconds, 13a was obtained at a conversion rate of 78% and a selectivity of 65%. When 4-aminophenol 13 and 2.2 molar equivalents of acetic anhydride were used as a substrate, Method SF was carried out at a temperature of 50 ° C., a pressure of 5 MPa, and a residence time of 9.9 seconds. A conversion of 100% and a selectivity of 99.5 were obtained. % N-acetyl compound 13a was obtained.

  From the above results, suitable reaction conditions strongly depend on the chemical structure of the substrate, and are deeply involved in being exothermic or endothermic. In the case of primary amines, this is usually an exothermic reaction, preferably carried out with 1.1 molar equivalents of carboxylic anhydride, Method AF1 or Method AF2, relative to the substrate, with a residence time of 1.1 seconds. The corresponding N-acyl compounds were obtained with a selectivity of 99% and a yield of 99% or more (Examples 11, 21, 22, and 24). Also in the case of secondary amine, it is usually an exothermic reaction, and 1.1 mol equivalent of carboxylic anhydride and residence time of 1.1 seconds with respect to the substrate by Method AF1, a conversion rate of 99.8%, The corresponding N-acylated product is obtained with a selectivity of 99% or more (Examples 1 and 3). However, when the steric effect or the resonance effect is strong, the carboxylic anhydride is less likely to attack the nitrogen atom or the unpaired electron on the nitrogen atom is reduced, so that the reactivity is lowered and the reaction is changed to an endothermic reaction. With AF1, the N-acyl compound cannot be obtained in good yield (Example 5). In that case, an N-acyl compound can be obtained by Method SF1 at a temperature of 100 ° C. to 200 ° C., a pressure of 5 MPa, and a residence time of 9.9 seconds (Examples 6 and 19).

  In the case of a tertiary amine, it is usually an exothermic reaction. According to Method AF1, the carboxylic anhydride is 1.1 molar equivalents with respect to the substrate and the residence time is about 1.1 seconds. The conversion rate slightly decreases due to the steric effect of 88% conversion and 100% selectivity (Examples 11 and 12). In the case of an aniline derivative, the steric effect of the substituent on the aromatic ring has little influence (Examples 7 and 9), but there is an influence of the resonance effect, and the electron withdrawing substituent reduces the unpaired electron on the nitrogen. , Reducing the reactivity and resulting in an endothermic reaction (Examples 7 vs. 15, 16), whereas the electron-donating substituents are somewhat endothermic (Example 7 vs. 15). 30). An aniline derivative in acetic acid forms an acetate salt, so that unpaired electrons on the nitrogen atom are reduced, N-acylation is difficult to proceed, and the steric effect is significant. Come (Examples 8 and 10).

  In addition, the thermal stability or hydrolyzability of the product N-acyl compound also affects the yield, and the higher the temperature, the better the yield is not necessarily (Example 1 vs. 2, Example 15 vs. Example 1). .14, Example 19 vs. 20, Example 22 vs. 23, Example 24 vs. 25). Therefore, it is better to add carboxylic anhydride in an equimolar amount or more and carry out at a lower temperature (Example 16 vs. 14, Example 30 vs. 29), but still, the flow type gives better results than the batch type ( Example 18 vs. 16).

  From the above examples, it was revealed that N-acyl compounds 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 an N-acyl compound is separated and recovered, while acetic acid and water are removed from the aqueous layer. It also became clear that a simple continuous separation method for separation and recovery by azeotropic distillation could be constructed.

  As described above in detail, the present invention uses a high-temperature and high-pressure fluid as a reaction solvent, a method for synthesizing an N-acyl compound without using an organic solvent from a carboxylic acid anhydride and a heterohydride, and a reaction composition thereof. In the conventional method, synthesis of an N-acyl compound from a hetero hydride and a carboxylic acid anhydride required adding a catalyst to an organic solvent and carrying out a reaction for several hours. By using the subcritical fluid / supercritical fluid shown in the invention, it has become possible to synthesize N-acyl compounds continuously at high speed without using a catalyst and without using an organic solvent. This brings about the merit that N-acyl compounds useful as fragrances, pharmaceuticals, and foods can be continuously produced in large quantities 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 an N-acyl compound is separated and recovered, while acetic acid and water are removed from the aqueous layer. It is possible to separate glacial acetic acid and water and to recycle water by a simple continuous separation method that separates and collects by azeotropic distillation. From these facts, it is possible to compress the initial cost and 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 N-acyl compounds useful as fragrances, pharmaceuticals, and foods.

This shows acylation of heterohydride using a catalyst / organic solvent. 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. The flow-type room temperature high pressure reactor used in the Example 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 40 Reactant liquid feed pump 41 Substrate liquid feed pump 42 Water liquid feed pump 43 reaction tee 44 piping 45 mixing tee 46 discharge piping 47 cooler 48 back pressure valve 49 recovery container 50 temperature sensor 51 temperature sensor

Claims (12)

  An N-acyl compound composition, which is a reaction composition of a carboxylic anhydride and a heterohydride, and has no catalyst and no organic solvent remaining.   A method for synthesizing an N-acyl compound from a carboxylic anhydride and a heterohydride. In the case of an exothermic reaction, a normal temperature fluid is reacted, and in the case of an endothermic reaction, a high temperature and high pressure subcritical fluid or supercritical fluid is reacted. A method for producing an N-acyl compound, which is used as a solvent and selectively synthesizes an N-acyl compound by a one-step synthesis reaction from a carboxylic anhydride and a heterohydride without using a catalyst.   The method for producing an N-acyl compound according to claim 2, wherein subcritical or supercritical water in a high temperature and high pressure state is used as a reaction solvent.   The method according to claim 2, wherein the heteroatom or substituted heteroatom in the heterohydride is hydrogen nitride (NH) or alkyl-substituted nitrogen (NR ′).   The N-acyl compound is selectively synthesized by adjusting the temperature or the amount of carboxylic anhydride with respect to the primary, secondary, or tertiary skeleton adjacent to the reaction point of the substrate. Method.   The method according to claim 2, 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, wherein water, acetic acid, other inorganic solvent, or an organic solvent or a mixed solvent of an inorganic solvent and an organic solvent is used as the normal temperature fluid, subcritical fluid or supercritical fluid.   The method according to claim 2, 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.   The method according to claim 2, wherein in the case of an exothermic reaction, the synthesis reaction is carried out by introducing a substrate and a reaction solvent into a flow-type room temperature high pressure apparatus and changing the reaction time in the range of 1 to 60 seconds.   A water feed pump for feeding water, a high-temperature and high-pressure flow cell, a reactant feed pump for feeding a substrate, a furnace body, a reactant introduction pipe for introducing the reactant into the furnace body, an exhaust liquid line for discharging the reaction solution, An N-acyl compound synthesizer comprising a cooling flange and a back pressure valve for setting pressure.   The apparatus for synthesizing an N-acyl compound according to claim 10, wherein a coil for water heating is provided in the case of an endothermic reaction.   The method according to claim 2, wherein after N-acylation, water is injected into the recovered aqueous solution and decanted, and after separation into an oil / water bilayer solution, an oil layer containing the N-acyl compound is separated and recovered, A simple continuous separation method in which acetic acid and water are separated and recovered from the aqueous layer by azeotropic distillation.

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