JP2010065020A - Method for producing aldol condensation compound - Google Patents

Abstract

<P>PROBLEM TO BE SOLVED: To provide a method for producing an aldol condensation compound in high efficiency even at normal temperature without using a metal compound catalyst and a non-polar organic solvent. <P>SOLUTION: The method for producing the aldol condensation compound comprises a step of condensing an aldehyde compound used as a raw material in the presence of a catalyst without using a solvent or in an aqueous solvent; provided that the method uses a catalyst comprising a basic amino acid expressed by formula (1) (X is methylene, ethylene, trimethylene, tetramethylene or group obtained by substituting any -CH<SB>2</SB>- group in the groups with -O- or -S-) or its salt; the aldehyde compound used as the raw material has a carbon number of ≥6; and concentrations of the catalyst and the aldehyde compound in a reaction liquid are adjusted in such a manner that a concentration of a Schiff base formed from the catalyst and the aldehyde compound becomes a critical micelle concentration or above. <P>COPYRIGHT: (C)2010,JPO&INPIT

Description

  The present invention relates to a process for producing aldol condensation compounds.

  Aldol condensation compounds are useful as synthetic intermediates and the like, and are synthesized from aldehyde compounds by a classic reaction called aldol condensation reaction. This aldol condensation reaction is carried out under heating conditions in an aqueous solution of a strong base such as sodium hydroxide. In addition, strong bases such as sodium ethoxide and lithium diisopropylamide and special reagents may be used as catalysts. Furthermore, since the raw material aldehyde compound is an organic compound, an organic solvent is often used instead of an aqueous solvent in order to allow the reaction to proceed smoothly in a uniform state.

  However, for environmental considerations, metal compounds should not be used as much as possible. In particular, in large-scale synthesis, although the amount used is relatively small, the treatment of metal compounds and strong bases after use becomes a problem. In addition, the normal aldol condensation reaction requires heating and a relatively long time.

  Therefore, the present inventors have conducted research and found that basic amino acids such as lysine and ornithine effectively act as catalysts in the aldol condensation reaction, as shown in Non-Patent Documents 1 and 2. More specifically, when an aldehyde was reacted in a nonpolar organic solvent such as chloroform in the presence of a basic amino acid such as lysine, the aldol compound was successfully produced at room temperature. In this reaction, normally, lysine or the like could effectively act as a catalyst even though it was not dissolved in a nonpolar organic solvent.

Hiroshi Watanabe et al., “Chemical Society of Japan Spring Annual Meeting Proceedings II”, 882 (2007) Takashi Morioka et al., “24th Synthetic Organic Chemistry Seminar Proceedings”, page 103 (2007)

  As described above, the present inventors have found that the aldol condensation reaction proceeds efficiently even when a safe basic amino acid such as lysine is used as a catalyst instead of a strong base containing a metal. Moreover, according to the knowledge at the time, in the aldol condensation reaction using a basic amino acid as a catalyst, good results were obtained in a nonpolar organic solvent such as chloroform and benzene, whereas in an polar solvent such as tetrahydrofuran. The reaction hardly progressed, and it did not react at all in water.

  However, in industrial large-scale synthesis, a large amount of solvent must also be used. Therefore, nonpolar organic solvents that adversely affect the environment should not be used as much as possible.

  Accordingly, an object of the present invention is to provide a method capable of efficiently producing an aldol condensation compound even at room temperature without using a metal compound catalyst or a nonpolar organic solvent.

  In the aldol condensation reaction using a basic amino acid as a catalyst, the present inventors first studied the cause of the reaction not proceeding in an aqueous solvent. As a result, it was found that the reaction does not proceed unless the concentration of the raw aldehyde compound and the basic amino acid is particularly sufficient. The reason is considered as follows. That is, the present inventors, as a reaction mechanism of the aldol condensation reaction using a basic amino acid, first, a Schiff base is formed between the basic amino acid and the raw aldehyde compound, the Schiff base and the raw aldehyde compound or the Schiff base I was thinking of something that would react to each other. According to the reaction mechanism, the Schiff base is inferior in water solubility compared to a basic amino acid, so that it cannot be sufficiently dispersed in an aqueous solvent, and the reaction does not proceed. Therefore, the present inventors use a raw material aldehyde compound having a large number of carbon atoms and a higher fat solubility, and the Schiff base exhibits a surfactant-like property, and the concentration thereof is sufficiently increased, in an aqueous solvent. By successfully forming micelle-like particles, the present invention was completed by successfully proceeding the reaction even at room temperature.

  The method for producing an aldol condensation compound according to the present invention includes a step of condensing a raw material aldehyde compound in the absence of a solvent or an aqueous solvent in the presence of a catalyst; a basic amino acid represented by the following formula (1) or a catalyst thereof: With salt

[Wherein X represents methylene, ethylene, trimethylene, tetramethylene, or a group in which any —CH ₂ — group in these groups is substituted with —O— or —S—];
Use raw aldehyde compounds with 6 or more carbon atoms; and adjust the concentration of the catalyst and raw aldehyde compound in the reaction solution so that the concentration of the Schiff base formed from the catalyst and raw aldehyde compound is equal to or higher than the critical micelle concentration. It is characterized by.

  In the method of the present invention, the concentration of the raw material aldehyde compound in the aqueous solvent is preferably 0.75 mol / L or more. If the concentration of the raw material aldehyde compound is increased to this range, micelle-like particles comprising a Schiff base can be formed more reliably.

  In the method of the present invention, the ratio of the catalyst to the raw material aldehyde compound is preferably 5 mol% or more and 50 mol% or less. If the amount of the catalyst is small, the Schiff base cannot sufficiently form micelle-like particles necessary for the progress of the reaction, and the reaction may not proceed efficiently. On the other hand, the larger the amount of the catalyst, the better the reaction proceeds.

  As the catalyst, lysine or ornithine, which is an abundant natural amino acid, is suitable.

  According to the method of the present invention, an aldol condensation compound can be efficiently produced with an environment-friendly design without using a harmful catalyst containing a metal and without heating in a solvent-free or water-based solvent. Therefore, the present invention is very useful industrially as it can be applied to industrial mass production of aldol condensation compounds useful as synthetic intermediates.

2 is a photograph of a reaction solution according to the method of the present invention. It turns out that it exists in an emulsified state. 2 is a phase contrast micrograph of the reaction solution shown in FIG. 1. It can be seen that micelle-like particles are formed. In the method of this invention, it is a phase-contrast micrograph of the reaction liquid when not using a solvent. It can be seen that micelle-like particles are formed.

  The method for producing an aldol condensation compound according to the present invention includes a step of condensing a raw material aldehyde compound in the absence of a solvent or an aqueous solvent in the presence of a catalyst.

  The water solvent used in the present invention refers to a solvent containing water and may be water alone or a mixed solvent of water and a water-miscible organic solvent. The kind of water here is not particularly limited, and any of distilled water, pure water, ultrapure water, tap water, and the like can be used. When a mixed solvent of water and a water-miscible organic solvent is used, the ratio of water in the mixed solvent is set to 10% by volume or more in order to more reliably form micelle-like particles. As the said ratio, 20 volume% or more is more preferable, 40 volume% or more is further more preferable, and 50 volume% or more is especially preferable. More preferably, only water is used as the solvent.

  On the other hand, when a raw material aldehyde having a particularly high hydrophobicity is used, a mixed solvent of water and a water-miscible organic solvent can be used in order to increase the solubility. Examples of the water-miscible organic solvent used by mixing with water include alcohols such as methanol and ethanol; ethers such as tetrahydrofuran; ketones such as acetone; amides such as dimethylformamide and dimethylacetamide. In addition, when using the mixed solvent of tetrahydrofuron etc. and water, it may isolate | separate into two layers by addition of a raw material aldehyde compound. In such a case, it is preferable not to use a mixed solvent or to increase the ratio of water. When the reaction is carried out using a mixed solvent, the reaction solution does not seem to be emulsified, but the formation of micelle-like particles can be confirmed by irradiating the reaction solution with a laser and light scattering.

  In the method of the present invention, the condensation step of the raw aldehyde compound can be carried out without a solvent. In the method of the present invention, a Schiff base is formed by a raw material aldehyde compound and a catalyst, and the reaction is allowed to proceed in micelle-like particles comprising the Schiff base. Since water is released when the Schiff base is formed, micelle-like particles composed of the Schiff base are formed and the reaction proceeds even when no aqueous solvent is used.

  In the method of the present invention, a basic amino acid represented by the following formula (1) or a salt thereof is used as a catalyst.

[Wherein X represents methylene, ethylene, trimethylene, tetramethylene, or a group in which any —CH ₂ — group in these groups is substituted with —O— or —S—]

The basic amino acid (1) in which X is ethylene is ornithine, and the basic amino acid (1) in which X is trimethylene is lysine, both of which are natural amino acids and can be easily obtained. Moreover, when the catalytic ability of the basic amino acid (1) in which X is tetramethylene or the basic amino acid (1) in which any —CH ₂ — group is substituted with —S— was evaluated, it was the same as that of lysine. The catalytic effect was obtained. On the other hand, dipeptides were synthesized from lysine and alanine and their catalytic ability was evaluated, but the catalytic effect was greatly reduced. The cause is considered to be that the distance between the terminal carboxy group and the terminal amino group is increased.

  The basic amino acid (1) may be a salt. The acid constituting the salt is not particularly limited, but for example, inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid; acetic acid, malonic acid, tartaric acid, methanesulfonic acid, benzenesulfonic acid, formic acid, toluene Organic acids such as sulfonate and trifluoroacetic acid can be used. However, in this case, in order to neutralize the acid, an equimolar base is added and reacted. Examples of such bases include potassium carbonate and sodium carbonate; potassium hydrogen carbonate and sodium hydrogen carbonate.

  Since the basic amino acid (1) has an asymmetric carbon, an optical isomer exists. In the method of the present invention, any of D-form, L-form and racemic form can be used, but if an optically active form is used, there is a possibility that a target compound with high optical purity can be selectively synthesized.

  As the aldehyde compound used as a raw material in the method of the present invention, one having 6 or more carbon atoms is used.

  The aldehyde group of the raw aldehyde compound reacts with the α-amino group of the basic amino acid to form a Schiff base. In the present invention, micelle-like particles are formed on the Schiff base to promote the reaction. Therefore, the Schiff base must have a surfactant-like property due to the hydrophobic portion derived from the raw material aldehyde compound, so that the raw material aldehyde compound has 6 or more carbon atoms. Further, since it is better to use a raw material aldehyde compound having higher hydrophobicity in the method of the present invention, a raw material aldehyde compound having 7 or more carbon atoms is preferably used, and further preferably a raw material aldehyde having 8 or more carbon atoms is used. Use compounds.

As the raw material aldehyde compound, both aliphatic aldehydes and aromatic aldehyde compounds can be used as long as they have 6 or more carbon atoms. As the aliphatic aldehyde, either a linear aliphatic aldehyde or a branched aliphatic aldehyde can be used. An aromatic aldehyde refers to an aliphatic aldehyde substituted with an aromatic group. Examples of the aromatic group include a phenyl group, a naphthyl group, a furanyl group, and a thiophenyl group. Further, as the raw material aldehyde compound, unless the hydrophobicity is excessively lowered, in the above aliphatic aldehyde or aromatic aldehyde compound, the —CH ₂ — group is substituted with —O— or —S—. May be.

  The upper limit of the carbon number of the raw material aldehyde compound is not particularly limited, but the main chain preferably has 20 or less carbon atoms. When the number of carbon atoms exceeds 20, the hydrophobicity of the Schiff base formed with the basic amino acid (1) increases excessively, which may make it difficult for the Schiff base to form micelle-like particles.

  In the method of the present invention, the aldol condensation reaction is promoted by adjusting the concentration of the catalyst and the raw aldehyde compound in the aqueous solvent so that the concentration of the Schiff base formed from the catalyst and the raw aldehyde compound is equal to or higher than the critical micelle concentration. Let me. That is, the raw material aldehyde compound and the basic amino acid (1) must be used in a sufficient amount so that the Schiff base formed by them can form micelle-like particles.

  The concentration of the raw material aldehyde compound to which the Schiff base can form micelle-like particles depends on the aqueous solvent used and the raw material aldehyde compound itself, but if the concentration in the reaction solution is 0.75 mol / L or more, it is more The formation of micelle-like particles with the Schiff base is surely possible. More preferably, it is 1.0 mol / L or more, More preferably, it is 1.5 mol / L or more.

  It can be said that as the amount of the basic amino acid (1) used increases, the concentration of the Schiff base increases, so that micelle-like particles are easily formed and the reaction efficiency increases. However, according to the knowledge of the present inventors, if the concentration of the basic amino acid (1) is too high, a by-product may be generated. Therefore, it is preferable that the usage-amount of basic amino acid (1) shall be 5 mol% or more and 50 mol% or less as a ratio with respect to a raw material aldehyde compound. More preferably, it is about 7 mol% or more and 20 mol% or less.

  In the present invention, a surfactant-like Schiff base is formed from the basic amino acid (1) and the raw material aldehyde compound, and the Schiff base is emulsified in the reaction solution to promote the reaction. Due to this emulsified state, the concentration of the Schiff base in the aqueous solvent is set to a critical micelle concentration or more. Since the critical micelle concentration varies depending on the basic amino acid (1) and the type of the raw aldehyde compound, it is preferably determined by preliminary experiments or the like. As a rough guide, when a raw material aldehyde compound having 6 carbon atoms is used, it can be about 5 mol / L or more and 10 mol / L or less. Moreover, when a raw material aldehyde compound having 7 or more carbon atoms is used, it can be set to about 0.5 mol / L or more and 5 mol / L or less.

  In the method of the present invention, when an aqueous solvent is used, the basic amino acid (1) and the raw aldehyde compound are added and reacted in the aqueous solvent, but the order of addition of each compound is not particularly limited. However, at least after mixing them, it is preferable to stir well to promote the formation of the Schiff base and the formation of micelle-like particles. Alternatively, it is also effective to perform normal stirring after ultrasonic irradiation for about several minutes. When the reaction is performed without a solvent, the basic amino acid (1) may be added while stirring the raw material aldehyde.

  The reaction temperature in the method of the present invention is not particularly limited and may be heated, but heating is not necessary because the reaction proceeds efficiently even at room temperature.

  The reaction time is not particularly limited, and may be determined in a preliminary experiment or continued until the starting compound disappears by chromatography or the like. However, since the method of the present invention is very efficient, usually 1 to The reaction is completed in about 5 hours.

  After completion of the reaction, the target aldol condensation compound may be purified by a conventional method. For example, since the aldol condensation compound according to the present invention is a condensate of aldehyde compounds having 6 or more carbon atoms and high fat solubility, the fat solubility is high. Therefore, the target compound can be extracted by adding an organic solvent immiscible with water such as chloroform, ethyl acetate, and diethyl ether to the reaction mixture after completion of the reaction for liquid separation. Alternatively, a saturated saline solution or a citric acid aqueous solution may be added to the reaction solution to separate it into two layers, and the organic phase containing the aldol condensation compound may be separated. Next, the obtained organic phase is dried over anhydrous sodium sulfate and concentrated, and the residue may be further purified by a conventional method such as chromatography or distillation.

  EXAMPLES Hereinafter, the present invention will be described more specifically with reference to examples. However, the present invention is not limited by the following examples, but may be appropriately modified within a range that can meet the purpose described above and below. It is also possible to implement, and they are all included in the technical scope of the present invention.

  Example 1 Aldol condensation of 3-phenylpropanal in water

  Lysine (28.2 mg, 0.19 mmol, 0.1 eq.) Was dissolved in water (2.0 ml). To the obtained aqueous solution, 3-phenylpropanal (258.8 mg, 1.93 mmol, 1.0 eq.) Was added and stirred at room temperature for 3 hours. After completion of the reaction, diethyl ether was added to separate the organic phase and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by flash column chromatography (eluent: ethyl acetate / hexane = 1/10) to obtain an aldol condensation compound (159.2 mg, yield 66%).

  Example 2 Aldol condensation of nonanal in water

  Lysine (21.2 mg, 0.15 mmol, 0.1 eq.) Was dissolved in water (1.9 ml). N-nonanal (206.3 mg, 1.45 mmol, 1.0 eq.) Was added to the obtained aqueous solution, and the mixture was stirred at room temperature for 3 hours. After completion of the reaction, diethyl ether was added and the organic phase was separated and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by flash column chromatography (eluent: ethyl acetate / hexane = 1/30) to obtain an aldol condensation compound (108.0 mg, yield 56%).

  Example 3 Aldol condensation of 3-phenylpropanal in water-methanol mixed solvent

  3-Phenylpropanal (254.0 mg, 1.89 mmol, 1.0 eq.), Methanol (0.95 ml) and water (0.95 ml) were mixed. While stirring the reaction mixture, lysine (27.7 mg, 0.19 mmol, 0.1 eq.) Was added and stirred at room temperature for 2 hours. After completion of the reaction, ether was added and the organic phase was separated and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by flash column chromatography (eluent: ethyl acetate / hexane = 1/10) to obtain an aldol condensation compound (172.0 mg, yield 73%).

  Example 4 Aldol condensation of 3-phenylpropanal in acetonitrile-water mixed solvent

  While stirring a mixture of 3-phenylpropanal (251.6 mg, 1.88 mmol, 1.0 eq.), Dry acetonitrile (1.9 ml) and water (211 μl), lysine (27.4 mg, 0.19 mmol, 0 .1 eq.) And further stirred at room temperature for 2 hours. After completion of the reaction, ethyl acetate was added and the organic phase was separated and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by flash column chromatography (eluent: ethyl acetate / hexane = 1/10) to obtain an aldol condensation compound (167.5 mg, yield 71%).

Comparative Example 1 Aldol condensation of 3-phenylpropanal in water To lysine (13.9 mg, 0.096 mmol), water (9.6 mL) was added and stirred at room temperature. After confirming dissolution of lysine, 3-phenylpropanal (128.8 mg, 0.96 mmol) was added and reacted at room temperature for 2 hours. Subsequently, ether was added for liquid separation, and the organic phase was dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was analyzed by NMR, but there was almost no signal derived from the aldol condensation compound.

  The reason why the reaction did not proceed is that since the amount of lysine and 3-phenylpropanal with respect to water as a solvent was small, the concentration of the Schiff base derived from these raw material compounds was not sufficient, and the micelle state effective for the reaction It is considered that was not formed.

Example 5 Aldol condensation in water The catalyst, lysine or ornithine (0.1 mmol, 0.3 mmol if the reaction was slow), was dissolved in water (1.0 mL). The raw material aldehyde shown in Table 1 was dropped while stirring the solution vigorously. After dropping, the reaction was allowed to proceed at room temperature for 2 hours. If the reaction did not proceed sufficiently even after 2 hours, the reaction time was extended. After completion of the reaction, an appropriate amount of water was added to the reaction solution, and extracted three times with diethyl ether. After the extracts were combined, the extract was washed with water and saturated brine, and dried over anhydrous sodium sulfate or anhydrous magnesium sulfate. After the solvent was distilled off, the residue was purified by flash column chromatography. When the unreacted raw material aldehyde was contained in the purified product, the yield of the aldol condensate and the E / Z ratio were calculated by ¹ H-NMR analysis. The results are shown in Table 1.

  As described above, according to the method of the present invention, an aldol condensation compound can be efficiently produced at room temperature even when safe water is used as a solvent.

  In addition, in the said reaction, the reaction liquid became a suspended state by addition of raw material aldehyde. Among the above reaction examples, a photograph of a reaction solution when 3-phenylpropanal is used as a raw material aldehyde and ornithine is used as a catalyst is shown in FIG. 1, and a phase contrast micrograph of the reaction solution is shown in FIG. The raw material aldehyde reacts with the catalyst to generate a Schiff base, and micelle-like particles composed of the Schiff base are formed, and the reaction solution becomes an emulsion. As a result, the reaction proceeds favorably by concentrating the Schiff base and the raw material aldehyde, which is the other reaction substrate, or enamine, which is a tautomer of the Schiff base, in the micelle-like particles. It is considered to be.

Example 6 Aldol condensation under heating in water Lysine (0.1 mmol) as a catalyst was dissolved in water (1.0 mL) and heated to the temperature shown in Table 2. The raw material aldehyde (1.0 mmol) shown in Table 2 was added dropwise while vigorously stirring the solution. After the dropwise addition, the mixture was reacted at the same temperature for 2 hours. After completion of the reaction, the reaction solution was cooled and treated in the same manner as in Example 5 to calculate the yield of the aldol condensate and the E / Z ratio. The results are shown in Table 2.

  When the results of Table 1 were compared with the results of Table 2, some improvement in yield was observed. Therefore, in the reaction of the present invention, it was found that the yield was better when heated, but the yield was not significantly improved, and it was revealed that the reaction proceeds sufficiently even at room temperature.

  Example 7 Aldol condensation of octanal in water using ultrasound

  The catalyst lysine (79.6 mg, 0.54 mmol, 0.1 eq.) Was dissolved in water (5.4 mL). Octanal (850 μL, 697.9 mg, 5.44 mmol) was added to the solution, and ultrasonic waves were irradiated for 1 minute with an ultrasonic homogenizer (Nippon Seiki Seisakusho, US-150T). Thereafter, the reaction solution was stirred with a magnetic stirrer at room temperature, and the reaction was continued for 2 hours. After completion of the reaction, water was added to the reaction solution, and extracted with ether three times. The extract was dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by flash column chromatography (eluent: ethyl acetate / hexane = 1/30), and the aldol condensation compound (E / Z = 97/3, yield: 492.7 mg, yield: 76%). )

  In the above results, the selectivity and yield of the E form were higher than in the case where the reaction was carried out in Example 5 without using ultrasonic waves. This result is considered to be the result of the formation of micelle-like particles promoted by the irradiation of ultrasonic waves and the production of a high-concentration emulsion suitable as a reaction field.

Example 8 Examination of reaction conditions In order to examine suitable reaction conditions, lysine (0.1 mmol) as a catalyst was dissolved in water (1.0 mL), and the solution was vigorously stirred, as shown in Table 3, Raw material aldehydes with different carbon numbers were added at various concentrations. After the addition, the mixture was reacted at room temperature for 2 hours. After completion of the reaction, the same treatment as in Example 5 was performed to calculate the yield of the aldol condensate. However, when an aldehyde having a small number of carbon atoms is used, there is an example in which an aldol condensation compound is isolated by distillation. The results are shown in Table 3.

  As shown in the above results, it can be said that the higher the concentration and the higher the concentration, the better the reaction yield.

  More specifically, in the case of an aldehyde having 8 or more carbon atoms, the yield greatly changed between a concentration of 0.5 mol / L and 1.0 mol / L. In the case of an aldehyde having 6 carbon atoms, the yield greatly changed between a concentration of 1.0 mol / L and 2.0 mol / L. In the case of the same concentration, the yield greatly changed between aldehydes having 6 and 7 carbon atoms at a concentration of 1.0 mol / L.

  Thus, the result that the high yield was dependent on the carbon number and density | concentration of a raw material aldehyde, ie, the ease of formation of a micelle-like particle, was obtained. In fact, the reaction solution when the yield was high quickly became emulsified, while the reaction solution when the yield was low was in a dilute suspension. Therefore, in the method of the present invention, it is necessary to adjust the concentration of the raw aldehyde and the catalyst so that the concentration of the Schiff base formed between the catalyst and the catalyst is equal to or higher than the critical micelle concentration according to the carbon number of the raw aldehyde .

Example 9 Aldol condensation without solvent The raw material aldehyde (1.0 mmol) shown in Table 4 was placed in a reactor, and lysine (0.1 mmol) was added while stirring at room temperature, and the mixture was reacted for 2 hours. Then, it processed similarly to the said Example 5, and calculated the yield and E / Z ratio of the aldol condensate. The results are shown in Table 4.

  As shown in the above results, it has been clarified that when lysine is used as a catalyst, the reaction proceeds well even in the absence of solvent.

  In the above reaction, the reaction solution became emulsified as lysine was added and the reaction proceeded. Among the above reaction examples, a phase contrast micrograph of the reaction solution when octanal is used as the raw material aldehyde is shown in FIG.

  As can be seen from FIG. 3, micelle-like particles are formed and the reaction proceeds even without solvent. This is considered to be due to the fact that water is released when the raw material aldehyde and lysine react to form a Schiff base, and the micelle-like particles comprising the Schiff base are dispersed in the generated water. The amount of water when no solvent is used is limited, and the micelle-like particle concentration is in a very high state, so even when hexanal having 6 carbon atoms is used, the raw material aldehyde concentration is 8 mol using an aqueous solvent. Yield (64%) equivalent to the yield at a high concentration of / L (see Table 3 in Example 8; 63%) is obtained. This fact supports that the same emulsion environment is the reaction field in the water-solvent system and the solvent-free system.

  Example 10 Aldol condensation using lysine hydrochloride as catalyst

  Lysine hydrochloride (33.0 mg, 0.18 mmol, 0.1 eq.) And potassium carbonate (25.0 mg, 0.18 mmol, 0.1 eq.) Were dissolved in water (1.8 mL). To the obtained aqueous solution, 3-phenylpropanal (242.4 mg, 238 μL, 1.81 mmol) was added and stirred at room temperature for 2 hours. After completion of the reaction, ethyl acetate was added and the organic phase was separated and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by flash column chromatography (eluent: ethyl acetate / hexane = 1/10) to obtain an aldol condensation compound (160.2 mg, yield 71%).

  Example 11 Aldol condensation using S-homolysine as catalyst

  S-homolysine (20.3 mg, 0.11 mmol, 0.1 eq.) Was dissolved in water (1.1 ml). To the obtained aqueous solution, 3-phenylpropanal (148.8 mg, 1.10 mmol) was added and stirred at room temperature for 2 hours. After completion of the reaction, ethyl acetate was added and the organic phase was separated and dried over anhydrous sodium sulfate. After the solvent was distilled off, the residue was purified by flash column chromatography (eluent: ethyl acetate / hexane = 1/10) to obtain an aldol condensation compound (96.3 mg, yield 69%).

  Example 12 Aldol condensation in water by post-treatment without extraction solvent

Lysine (23.8 mg, 0.16 mmol, 0.1 eq.) Was added to water (1.63 mL) and stirred at room temperature. After confirming that lysine had dissolved, octanal (253 μL, 207.6 mg, 1. 60 mmol, 1.0 eq.) Was added and reacted for 2 hours. A 5% aqueous tartaric acid solution (3 mL) was added to the reaction system to separate the organic phase and the aqueous phase, and the organic phase was taken out. The organic phase was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The obtained residue was purified by flash column chromatography (hexane / ethyl acetate = 40/1), and the yield was calculated from the aldehyde peak ratio of ¹ H-NMR. The yield was 60% (115.7 mg, 0.49 mmol), and E / Z was 87/13.

Claims (4)

A method for producing an aldol condensation compound comprising:
Condensing the raw aldehyde compound in the absence of a catalyst or in an aqueous solvent in the presence of a catalyst;
A basic amino acid represented by the following formula (1) or a salt thereof is used as a catalyst.
[Wherein X represents methylene, ethylene, trimethylene, tetramethylene, or a group in which any —CH ₂ — group in these groups is substituted with —O— or —S—];
The raw material aldehyde compound having 6 or more carbon atoms is used; and the concentration of the catalyst and raw material aldehyde compound in the reaction solution is adjusted so that the concentration of the Schiff base formed from the catalyst and the raw material aldehyde compound is equal to or higher than the critical micelle concentration. ;
The manufacturing method characterized by the above-mentioned.   The manufacturing method of Claim 1 which makes the density | concentration of the raw material aldehyde compound in a reaction liquid 0.75 mol / L or more.   The manufacturing method of Claim 1 or 2 which makes the ratio of the catalyst with respect to a raw material aldehyde compound 5 mol% or more and 50 mol% or less.   The production method according to claim 1, wherein lysine or ornithine is used as the catalyst.