Aqueous reaction solvents used in organic chemical reactions

Abstract

To provide an aqueous reaction solvent which allows organic chemical reaction to be performed efficiently.SOLUTION: An aqueous solution containing a carboxybetaine represented by general formula (1) is used as a reaction solvent, so that the reaction efficiency of organic chemical reaction is enhanced.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to an aqueous reaction solvent capable of efficiently carrying out an organic chemical reaction, and also to a method for carrying out an organic chemical reaction using the aqueous reaction solvent. [Background technology]

[0002] Conventionally, organic solvents have been widely used as solvents for organic chemical reactions. In particular, in the pharmaceutical industry, it is said that 25 to 100 kg of waste is generated to manufacture 1 kg of product, of which 80% is organic solvent (Non-Patent Document 1). If the organic solvents used in organic chemical reactions could be replaced with water, it is expected that there would be positive effects in terms of the environment and the economy.

[0003] On the other hand, water is an attractive solvent because of its characteristics such as cheapness, nonflammability, nontoxicity, and environmental compatibility, but it has difficulties in terms of solubility of substrates and reactivity of organic chemical reactions, and is therefore highly limited as a solvent for organic chemical reactions. It has been reported that aqueous solvents containing surfactants can be used as solvents for organic chemical reactions. When performing organic chemical reactions using aqueous solvents containing surfactants, it is considered to be good to form large micelles in the aqueous solvent, and TPGS-750-M and NOK have been reported as surfactants that are optimal for forming such micelles (Non-Patent Documents 2 and 3). However, even if an organic chemical reaction is performed using an aqueous solvent containing TPGS-750-M or NOK, there are disadvantages in that the reaction efficiency is not high and foaming specific to surfactants occurs during the reaction accompanied by stirring. In particular, if foaming occurs during the reaction, the volume of the foam affects the size of the reaction vessel when synthesizing on a large scale, leading to a decrease in production efficiency.

[0004] In light of the background of the conventional techniques, there is a strong demand for the development of an aqueous reaction solvent capable of efficiently carrying out organic chemical reactions. [Prior art documents] [Non-patent literature]

[0005] [Non-Patent Document 1] Kevin H. Shaughnessy et al.,Current Organic Chemistry,2005,9,585-604 [Non-Patent Document 2] BHLipshutz et al.,J.Org.Chem.,2011,76,4379-4391 [Non-Patent Document 3] P.Klumphu,BH,Lipshutz,J.Org.Chem.,2014,79,888-900 Summary of the Invention [Problem to be solved by the invention]

[0006] An object of the present invention is to provide an aqueous reaction solvent capable of efficiently carrying out organic chemical reactions. [Means for solving the problem]

[0007] The present inventors have conducted extensive research to solve the above problems and have found that the efficiency of organic chemical reactions can be improved by using an aqueous solution containing a carboxybetaine having a specific structure as a reaction solvent. The present invention has been completed based on this finding and further research.

[0008] That is, the present invention provides the following aspects. Item 1. A reaction solvent for organic chemical reactions, comprising an aqueous solution containing a carboxybetaine represented by the following general formula (1): [ka] [In the general formula (1), R 1 , R 2 , and R 3 each represents the same or different alkyl group, and R 1 , R 2 , and R 3The total number of carbon atoms in the alkyl group is 9 to 15, and R 4 is an alkylene group having 1 to 5 carbon atoms.] Item 2. In the general formula (1), R 1 , R 2 , and R 3 are the same or different and each is an alkyl group having 3 to 5 carbon atoms, and R 4 is a methylene group. Item 3. In the general formula (1), R 1 , R 2 , and R 3 is an alkyl group having 4 or 5 carbon atoms, and R 4 Item 3. The reaction solvent according to Item 1 or 2, wherein is a methylene group. Item 4. The reaction solvent according to any one of Items 1 to 3, wherein the concentration of the carboxybetaine represented by the general formula (1) in the aqueous solution is 0.01 to 3 M. Item 5. A method for carrying out an organic chemical reaction, comprising using the reaction solvent according to any one of items 1 to 4. Effect of the Invention

[0009] According to the present invention, the reaction efficiency can be improved by using an aqueous solution of carboxybetaine having a specific structure as a reaction solvent for an organic chemical reaction. Furthermore, according to the present invention, since an aqueous solvent is used as a reaction solvent for an organic chemical reaction, the environmental problems and safety concerns that are problematic in organic chemical reactions using organic solvents can be eliminated. Furthermore, conventional aqueous solvents use surfactants such as TPGS-750-M and NOK, which have the drawback of foaming during the reaction. However, the reaction solvent of the present invention can suppress foaming during the reaction, so that even if an organic chemical reaction is carried out on a large scale, the decrease in production efficiency due to foaming can be suppressed. [Brief description of the drawings]

[0010] [Figure 1] This is a photographic image showing the appearance during the Suzuki-Miyaura coupling reaction using 2 wt % betaine 5 aqueous solution, 2 wt % TPGS-750-M aqueous solution, and 2 wt % NOK aqueous solution as reaction solvents. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0011] 1. Reaction Solvent The reaction solvent of the present invention is a reaction solvent used in organic chemical reactions, and is characterized in that it contains an aqueous solution containing a carboxybetaine represented by general formula (1). The reaction solvent of the present invention will be described in detail below.

[0012] [Composition of reaction solvent] The reaction solvent of the present invention contains a carboxybetaine represented by the following general formula (1): By including such a specific carboxybetaine in the aqueous reaction solvent, it becomes possible to increase the reaction efficiency of the organic chemical reaction. [ka]

[0013] In the general formula (1), R 1 , R 2 , and R 3 each represents the same or different alkyl group, and R 1 , R 2 , and R 3 The total number of carbon atoms in the alkyl groups is 9 to 15. 1 , R 2 , and R 3 "Total number of carbon atoms in the alkyl group of R 1 The number of carbon atoms in the alkyl group and R 2 The number of carbon atoms in the alkyl group and R 3 R is the total number of carbon atoms in the alkyl groups. 1 , R 2 , and R 3 By using a carboxybetaine having a total number of carbon atoms in the alkyl groups of R that satisfies the above range, it is possible to improve the reaction efficiency of organic chemical reactions. 1 , R 2 , and R 3The total number of carbon atoms in the alkyl group is preferably 10 to 15, more preferably 11 to 15, further preferably 12 to 15, and even more preferably 12 or 15.

[0014] R 1 , R 2 , and R 3 The number of carbon atoms in each of the alkyl groups is not particularly limited as long as the total number of carbon atoms falls within the above range, and is, for example, 1 to 8, preferably 2 to 7, more preferably 3 to 6, even more preferably 3 to 5, and even more preferably 4 or 5.

[0015] R 1 , R 2 , and R 3 When the alkyl group has 3 or more carbon atoms, the alkyl group may be either linear or branched, and is preferably linear.

[0016] In the general formula (1), R 4 is an alkylene group having 1 to 5 carbon atoms. 4 is preferably an alkylene group having 1 to 3 carbon atoms, more preferably a methylene group (-CH 2 -) or ethylene group (-CH 2 -CH 2 -), and more preferably a methylene group.

[0017] A preferred example of the carboxybetaine represented by the general formula (1) is a carboxybetaine represented by the general formula (1), 1 , R 2 , and R 3 are the same or different and each is an alkyl group having 3 to 5 carbon atoms, and R 4 is a methylene group; more preferably, in the general formula (1), R 1 , R 2 , and R 3 are the same or different and each is an alkyl group having 4 or 5 carbon atoms (preferably a linear butyl group or pentyl group), and R 4 is a methylene group.

[0018] In the reaction solvent of the present invention, the carboxybetaine represented by the general formula (1) may be used alone having one type of structure, or may be used in combination of two or more types of structures.

[0019] A method for producing the carboxybetaine represented by the general formula (1) is publicly known, for example, in JP-A-2009-96766, and can be derived from a publicly known organic synthesis method.

[0020] In the reaction solvent of the present invention, the concentration of the carboxybetaine represented by general formula (1) may be appropriately set depending on the structure of the carboxybetaine employed and the type of organic chemical reaction, and may be, for example, 0.01 to 3 M. From the viewpoint of further improving the reaction efficiency of the organic chemical reaction, the concentration of the carboxybetaine represented by general formula (1) in the reaction solvent of the present invention is preferably 0.05 to 3 M, more preferably 0.1 to 2 M, even more preferably 0.1 to 1 M, still more preferably 0.25 to 1 M, and particularly preferably 0.5 to 1 M.

[0021] The reaction solvent of the present invention is an aqueous solvent and therefore contains water. In addition, the reaction solvent of the present invention may contain additives such as a surfactant, if necessary, within a range that does not impair the effects of the present invention.

[0022] [Uses of reaction solvents] The reaction solvent of the present invention is not particularly limited with respect to the type of organic chemical reaction to which it is applied, and may be applied to any organic chemical reaction. Examples of organic chemical reactions to which the reaction solvent of the present invention is applied include Suzuki-Miyaura coupling, Ullmann coupling, Heck reaction, Stille coupling, Sonogashira coupling, Hiyama coupling, Kumada cross-coupling, McMurry coupling, Wittig reaction, acetylation reaction (amine, alcohol, phenol, thiol, thiophenol, etc.), electrophilic substitution reaction of aromatics (halogenation, nitration, nitrosation, sulfonation, diazotization, Friedel-Crafts acylation, Friedel-Crafts acylation, etc.), and the like. Alkylation, formylation (Vilsmeier reaction, Gattermann reaction, Duff reaction, Reimer-Tsiemann reaction, etc.), hydride reduction reaction (reduction reaction of aldehydes, carboxylic acids, esters, ketones, etc.), metal reduction reaction (nitro, ketones, aldehydes, alkenes, etc. (Clemmensen reduction, Birch reduction, Wolf-Kishner reduction, etc.), ozone oxidation (alkenes, etc.), chloric acid / hypochlorite oxidation, peracid oxidation (alkenes, primary hydroxyl groups, etc.), Swan oxidation, Dakin oxidation, Dess-Martin oxidation, Wacker oxidation, metal oxidation reaction (potassium permanganate, manganese oxide, potassium dichromate, Jones oxidation, etc.), O-alkylation reaction (Williamson ether synthesis reaction, etc.), N-alkylation reaction, S-alkylation reaction, hydrolysis reaction (nitriles, amides, esters, thioesters, glycosides, ethers, acetals, ketals, carbamates, phosphate esters, etc.), Diels-Alder reaction, retro-Diels-Alder reaction, rearrangement reaction (pinacol-pinacolone rearrangement, allylic rearrangement, Wolff rearrangement, benzyl-benzilic acid rearrangement, Faborski rearrangement, Pummerer rearrangement, Loop rearrangement, Mayer-Schuster rearrangement, Fritz-Battenburg-Biechel rearrangement, Smiles rearrangement, Fries rearrangement, Beckmann rearrangement, Curtius rearrangement, Rossen rearrangement, Hoffmann rearrangement, Schmidt reaction, Baeyer-Willieger oxidation, Dakin reaction, dienone-phenol rearrangement, Stevens rearrangement, Sommeret-Hauser rearrangement, Wittig rearrangement, Claisen rearrangement, Cope rearrangement, benzidine rearrangement, Chan rearrangement, Dimroth rearrangement, Payne rearrangement, etc.), decarboxylation reaction, radical halogenation, radical addition reaction of hydrogen halide or halogen, hydroboration reaction,Examples of such reactions include halohydrin reaction, Grignard reaction, aldol condensation, Mukaiyama aldol condensation, Claisen condensation, benzoin condensation, Dieckmann condensation, Stobbe condensation, Craneke pyridine synthesis, Michael addition, Sandmeyer reaction, Mitsunobu reaction, Mannich reaction, Amadori reaction, Robinson cyclization, Wharton cleavage, Gabriel synthesis, azidation reaction, olefin metathesis reaction, Hoffman elimination, Cook reaction, asymmetric synthesis reaction (Sharpless asymmetric amination, Jacobsen-Katsuki asymmetric epoxidation, Rausch asymmetric allylation, etc.), polymerization reaction (radical polymerization, cationic polymerization, anionic polymerization, coordination polymerization, ring-opening polymerization, chain condensation polymerization, polycondensation, polyaddition, addition condensation, living radical polymerization, living cationic polymerization, living anionic polymerization, living coordination polymerization, etc.), etc.

[0023] These chemical reactions are well known, and those skilled in the art can understand the reaction mechanisms of these chemical reactions based on known techniques.

[0024] For example, the Suzuki-Miyaura coupling is a chemical reaction in which an organoboron compound is cross-coupled with an aryl halide to give a biphenyl derivative.

[0025] The Wittig reaction is a chemical reaction in which a phosphorus ylide reacts with a carbonyl compound to produce an alkene.

[0026] An acetylation reaction is a chemical reaction in which a compound having a hydroxyl group, an amino group, and / or a thiol group is reacted with an acetylating agent such as acetic anhydride to replace the hydrogen atoms of the hydroxyl group and / or amino group with acetyl groups.

[0027] Among aromatic electrophilic substitution reactions, for example, a halogenation reaction is a chemical reaction in which a raw material compound is reacted with a halogenating agent to obtain a halide. In the present invention, the halogenation reaction includes fluorination, chlorination, bromination, iodination, etc.

[0028] Among aromatic electrophilic substitution reactions, for example, the Friedel-Crafts acylation reaction is a chemical reaction in which an aromatic ring compound is acylated by reacting an acid halide or acid anhydride with the aromatic ring compound in the presence of a Lewis acid.

[0029] A hydride reduction reaction is a chemical reaction that uses a hydrogen donor as a nucleophile to reduce a compound.

[0030] Among O-alkylation reactions, for example, the Williamson ether synthesis reaction is a chemical reaction in which an ether is synthesized by reacting an alcohol with a compound having a leaving group, such as a halide or sulfonate, in the presence of a strong base.

[0031] The N-alkylation reaction is a chemical reaction in which a compound having an amino group is reacted with a compound having an alkyl halide to alkylate the amino group.

[0032] Among hydrolysis reactions, for example, the hydrolysis reaction of a nitrile is a chemical reaction in which the cyano group of a compound having a cyano group is converted into an amide group or a carboxyl group in the presence of an acid or a base.

[0033] In addition, the structure of the substrate to be subjected to an organic chemical reaction using the reaction solvent of the present invention is not particularly limited, and may be, for example, any of acyclic compounds, monocyclic compounds, polycyclic compounds, monoheterocyclic compounds, and polycyclic compounds.

[0034] In an organic chemical reaction using the reaction solvent of the present invention, reaction conditions such as substrate concentration, catalyst to be used, reaction temperature, reaction time, etc. can be appropriately set by a person skilled in the art based on well-known techniques, etc.

[0035] 2. Organic Chemical Reaction Methods The organic chemical reaction method of the present invention is a method for carrying out an organic chemical reaction using the above-mentioned reaction solvent. The type of organic chemical reaction in the organic chemical reaction method of the present invention, the substrate to be used, etc. are as described in the above section "1. Reaction solvent". EXAMPLES

[0036] The present invention will be specifically described below by way of examples, but the present invention is not limited to these in any way.

[0037] Manufacturing example: Manufacturing of various carboxybetaines Carboxybetaines 1 to 5 shown below were synthesized with reference to the method described in JP 2009-96766 A. Carboxybetaine 1 is a compound represented by the general formula (1) R 1 ~R 3 is a methyl group, and R 4 is a methylene group, and carboxybetaine 2 is a compound represented by the general formula (1) 1 ~R 3 is an ethyl group, and R 4 is a methylene group, and carboxybetaine 3 is a compound represented by the general formula (1) 1 ~R 3 is a propyl group, and R 4 In the general formula (1), R is a methylene group, and carboxybetaine 4 is a compound represented by the general formula (1), 1 ~R 3 is a butyl group, and R 4 is a methylene group, and carboxybetaine 5 is a compound represented by the general formula (1) 1 ~R 3 is a pentyl group, and R 4 is a methylene group. [ka]

[0038] Example 1: Suzuki-Miyaura coupling reaction of carboxybetaine 5 in aqueous solution In a 10 mL screw-cap test tube, 50.2 mg (0.25 mmol) of 4-bromo-N,N-dimethylaniline (Tokyo Chemical Industry Co., Ltd., model number B0585-25G), 55.1 mg (0.25 mmol) of 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (Tokyo Chemical Industry Co., Ltd., model number T1951-5G), and Pd(PPh 3 ) 4(Colonial Metals, model number 5094) 14.4 mg (0.0125 mmol, 0.7 mol%), potassium carbonate (Fujifilm Wako Pure Chemical, model number 162-03495) 173.3 mg (1.25 mmol), 2.0 M carboxybetaine 5 aqueous solution 1.5 ml or distilled water 1.5 ml were added, and the mixture was heated and stirred at 60 ° C under a nitrogen atmosphere for 1 hour to carry out the Suzuki-Miyaura coupling reaction. After cooling the reaction solution, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel (Fuji Silysia, model number PSQ100AB)) and chloroform (Fujifilm Wako Pure Chemical, model number 033-02617): hexane (Fujifilm Wako Pure Chemical, model number 080-00427) = 2: 1), and dried under reduced pressure to obtain a reddish brown solid. [ka]

[0039] Regarding the product (reddish brown solid), 1 Identification was performed by 1 H NMR, and it was confirmed that a product with the desired structure was obtained (Table 1).

[0040] [Table 1]

[0041] The yields and yields of the products are shown in Table 2. The yield of the Suzuki-Miyaura coupling reaction in distilled water was 38%, whereas the yield of the Suzuki-Miyaura coupling reaction in an aqueous solution of carboxybetaine 5 was 63%, which is a 25% increase in yield compared to distilled water.

[0042] [Table 2]

[0043] Example 2: Acetylation reaction of 1-naphthol in aqueous solution of carboxybetaine 5 14.4 mg (0.1 mmol) of 1-naphthol (manufactured by Fujifilm Wako Pure Chemical Industries, model number 148-00215), 94.5 μl (1 mmol) of acetic anhydride (manufactured by Fujifilm Wako Pure Chemical Industries, model number 017-00273), 1.0 ml of 2.0 M carboxybetaine 5 aqueous solution or 1.0 ml of distilled water were added to a 10 mL screw-cap test tube and heated and stirred at 60°C for 20 hours to carry out the acetylation reaction of 1-naphthol. After the reaction solution was allowed to cool, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel, chloroform:hexane = 1:3) and dried under reduced pressure to obtain a white solid. [ka]

[0044] Regarding the product (white solid), 1 Identification was performed by 1 H NMR, and it was confirmed that a product with the desired structure was obtained (Table 3).

[0045] [Table 3]

[0046] The yield and amount of the product are shown in Table 4. When 1-naphthol was acetylated in distilled water, the reaction did not proceed at all, whereas when 1-naphthol was acetylated in an aqueous solution of carboxybetaine 5, the yield was 83%, and the yield was significantly higher in the aqueous solution of carboxybetaine 5 than in distilled water.

[0047] [Table 4]

[0048] Example 3: Aromatic bromination reaction in aqueous solution of carboxybetaine 5 14.4 mg (0.1 mmol) of 1-naphthol (manufactured by Fujifilm Wako Pure Chemical Industries, model number 148-00215), 17.8 mg (0.1 mmol) of N-bromosuccinimide (manufactured by Fujifilm Wako Pure Chemical Industries, model number 025-07235), 1.0 ml of 2.0 M carboxybetaine 5 aqueous solution or 1.00 ml of distilled water were added to a 10 mL screw-cap test tube and heated and stirred at 60°C for 6 hours to carry out the bromination reaction of 1-naphthol. After the reaction solution was allowed to cool, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel, chloroform:hexane = 2:1) and dried under reduced pressure to obtain a yellow solid. [ka]

[0049] Regarding the product (yellow solid), 1 Identification was performed by 1 H NMR, and it was confirmed that a product with the desired structure was obtained (Table 5).

[0050] [Table 5]

[0051] The yields and masses of the products are shown in Table 6. The yield of bromination of 1-naphthol in distilled water was 19%, whereas the yield of bromination of 1-naphthol in an aqueous solution of carboxybetaine 5 was 31%, a 12% increase in yield when compared to distilled water.

[0052] [Table 6]

[0053] Example 4: Reduction of aldehydes in aqueous solution of carboxybetaine 5 In a 10 mL screw-top test tube, add 18.5 mg (0.1 mmol) of o-bromobenzaldehyde (manufactured by Fujifilm Wako Pure Chemical Industries, model number 020-13172) and NaBH 4(FUJIFILM Wako Pure Chemical Industries, Ltd., Model No. 192-01472) 37.8 mg (0.1 mmol), 1.0 ml of 2.0 M carboxybetaine 5 aqueous solution or 1.0 ml of distilled water were added and stirred at 30° C. for 3 hours to carry out the reduction reaction of the aldehyde. After the reaction was completed, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel, chloroform:methanol (FUJIFILM Wako Pure Chemical Industries, Ltd., Model No. 136-01837) = 20:1), and dried under reduced pressure to obtain a white solid. [ka]

[0054] Regarding the product (white solid), 1 Identification was performed by 1 H NMR, and it was confirmed that a product with the desired structure was obtained (Table 7).

[0055] [Table 7]

[0056] The yields and yields of the products are shown in Table 8. When the reduction reaction of the aldehyde was carried out in distilled water, the yield was 23%, whereas when the reduction reaction of the aldehyde was carried out in an aqueous solution of carboxybetaine 5, the yield was 54%, which means that the yield was increased by 31% when using the aqueous solution of carboxybetaine 5 compared to distilled water.

[0057] [Table 8]

[0058] Example 5: Aromatic Friedel-crafts acylation reaction of carboxybetaine 5 in aqueous solution In a 10 mL screw-top test tube, 10.6 μl (0.1 mmol) of toluene (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., model number 204-01866) and AlCl 3(FUJIFILM Wako Pure Chemical Industries, model number 013-01892) 13.3 mg (0.1 mmol), 1.0 ml of 2.0 M carboxybetaine 5 aqueous solution or 1.0 ml of distilled water were added, and the mixture was heated and stirred at 80°C under a nitrogen atmosphere for 8 hours to carry out the Friedel-Crafts acylation reaction. After the reaction solution was allowed to cool, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel, chloroform:hexane = 1:2) and dried under reduced pressure to obtain a white solid. [ka]

[0059] Regarding the product (white solid), 1 Identification was performed by 1 H NMR, and it was confirmed that a product with the desired structure was obtained (Table 9).

[0060] [Table 9]

[0061] The yield and yield of the product are shown in Table 10. The Friedel-Crafts acylation reaction in distilled water did not proceed at all, whereas the Friedel-Crafts acylation reaction in an aqueous solution of carboxybetaine 5 gave a yield of 14%, which is a marked increase in yield when using an aqueous solution of carboxybetaine 5 compared to distilled water.

[0062] [Table 10]

[0063] Example 6 Williamson ether synthesis reaction in aqueous carboxybetaine solution 14.4 mg (0.1 mmol) of 2-naphthol (manufactured by Fujifilm Wako Pure Chemical Industries, model number 149-00245), 18.6 mg (0.1 mmol) of methyl p-toluenesulfonate (manufactured by Fujifilm Wako Pure Chemical Industries, model number T0269-500G), 1.0 ml of 2.0 M carboxybetaine 5 aqueous solution or 1.0 ml of distilled water were added to a 10 mL screw-cap test tube, and the mixture was heated and stirred at 80°C for 8 hours to carry out the Williamson ether synthesis reaction. After the reaction solution was allowed to cool, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel, chloroform:hexane = 1:5) and dried under reduced pressure to obtain a white solid. [ka]

[0064] Regarding the product (white solid), 1 Identification was performed by 1 H NMR, and it was confirmed that a product with the desired structure was obtained (Table 11).

[0065] [Table 11]

[0066] The yield and yield of the product are shown in Table 12. When the Williamson ether synthesis reaction of aldehyde was carried out in distilled water, the yield was 12%, whereas when the Williamson ether synthesis reaction was carried out in an aqueous solution of carboxybetaine 5, the yield was 100%, which means that the yield was increased by 88% when using an aqueous solution of carboxybetaine 5 compared to distilled water.

[0067] [Table 12]

[0068] Example 7: N-alkylation reaction of carboxybetaine 5 in aqueous solution A 10mL screw-top test tube was charged with 36.5μl (0.4mmol) of aniline (Tokyo Chemical Industry Co., Ltd., model number A0463-500G), 12.7mg (0.1mmol) of benzyl chloride (Fujifilm Wako Pure Chemical Industries, Ltd., model number 020-01386), 1.0ml of 2.0M carboxybetaine 5 aqueous solution or 1.0ml of distilled water, and heated and stirred at 80℃ for 4 hours to carry out the N-alkylation reaction of aniline. After the reaction solution was allowed to cool, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel, chloroform:hexane=1:1), and dried under reduced pressure to obtain a white solid. [ka]

[0069] Regarding the product (white solid), 1 Identification was performed by 1 H NMR, and it was confirmed that a product with the desired structure was obtained (Table 13).

[0070] [Table 13]

[0071] The yields and masses of the products are shown in Table 14. The yield of the N-alkylation reaction of aniline in distilled water was 24%, whereas the yield of the N-alkylation reaction of aniline in an aqueous solution of carboxybetaine 5 was 46%, which means that the yield of the aqueous solution of carboxybetaine 5 was increased by 22% compared to distilled water.

[0072] [Table 14]

[0073] Example 8: Wittig reaction of carboxybetaine 5 in aqueous solution In a 10mL screw-top test tube, 43.9mg (0.1mmol) of (1-naphthylmethyl)triphenylphosphonium chloride (Tokyo Chemical Industry Co., Ltd., model number N0700-5G), 10.2μl (0.1mmol) of benzaldehyde (Fujifilm Wako Pure Chemical Industries, Ltd., model number 025-12206), 1.0ml of 2.0M betaine 5 aqueous solution or 1.0ml of distilled water were added, and the mixture was heated and stirred at 60℃ for 4 hours to carry out the Wittig reaction. After the reaction solution was allowed to cool, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel, chloroform:hexane=1:3) and dried under reduced pressure to obtain a white solid. [ka]

[0074] Regarding the product (white solid), 1 Identification was performed by 1 H NMR, and it was confirmed that a product with the desired structure was obtained (Table 15).

[0075] [Table 15]

[0076] The yields and masses of the products are shown in Table 16. The yield of the Wittig reaction in distilled water was 29%, whereas the yield of the Wittig reaction in an aqueous solution of carboxybetaine 5 was 55%, which means that the yield of the aqueous solution of carboxybetaine 5 was increased by 26% compared to distilled water.

[0077] [Table 16]

[0078] Example 9: Hydrolysis of nitriles in aqueous solution of carboxybetaine 5 11.8 mg (0.1 mmol) of 4-aminobenzonitrile (FUJIFILM Wako Pure Chemical Industries, model number 014-10651), 40.0 mg (1 mmol) of NaOH (FUJIFILM Wako Pure Chemical Industries, model number 198-13765), 1.0 ml of 2.0 M betaine 5 aqueous solution or 1.0 ml of distilled water were added to a 10 mL screw-top test tube and heated and stirred at 60°C for 4 hours to carry out the hydrolysis reaction of the nitrile. After the reaction solution was allowed to cool, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel, chloroform:hexane = 1:2) and dried under reduced pressure to obtain a white solid. [ka]

[0079] Regarding the product (white solid), 1 Identification was performed by 1 H NMR, and it was confirmed that a product with the desired structure was obtained (Table 17).

[0080] [Table 17]

[0081] The yields and masses of the products are shown in Table 18. When the hydrolysis reaction of the nitrile was carried out in distilled water, the yield was 22%, whereas when the hydrolysis reaction of the nitrile was carried out in an aqueous solution of carboxybetaine 5, the yield was 100%, which means that the yield was increased by 78% in the aqueous solution of carboxybetaine 5 compared to distilled water.

[0082] [Table 18]

[0083] [Summary of Examples 1 to 9] As shown in Examples 1 to 9, it was shown that the reaction yield was improved by using an aqueous solution containing carboxybetaine represented by general formula (1) as a reaction solvent in various organic chemical reactions. In other words, it was proven that an aqueous solution containing carboxybetaine represented by general formula (1) effectively functions as a reaction solvent for various organic chemical reactions.

[0084] Example 10: Effect of the starting substrate used in the Suzuki-Miyaura coupling reaction on the yield In order to consider the influence of the chemical structure of the raw material used in the Suzuki-Miyaura coupling reaction, the Suzuki-Miyaura coupling reaction was carried out in the same manner as in Example 1, except that 4-bromo-N,N-dimethylaniline was replaced with raw material substrates having a polycyclic structure, a heterocyclic structure, a positional isomer of the same substituent, a different functional group structure, etc. (Table 19) and the reaction conditions were set to 60°C and 21 hours, and the reaction yield was calculated.

[0085] The results are shown in Table 19. It was shown that when the Suzuki-Miyaura coupling reaction was carried out in an aqueous solution of carboxybetaine 5, the yield increased for all raw substrates compared to water. In other words, it was found that the improvement in yield in the reaction using an aqueous solution of carboxybetaine 5 as the solvent was not affected by the structure of the raw substrate.

[0086] [Table 19]

[0087] Example 11: Effect of differences in the chemical structure of carboxybetaine on the yield of the Suzuki-Miyaura coupling reaction The Suzuki-Miyaura coupling reaction was carried out in the same manner as in Example 1, except that the concentration of carboxybetaine used as the reaction solvent was not changed (2.0 M) and the type of carboxybetaine added was changed to carboxybetaine 1 to 4, and the reaction yield was calculated.

[0088] The results are shown in Table 20. The reaction in aqueous carboxybetaine solutions differed depending on the structure of the carboxybetaine. Compared to distilled water, the increase in yield for carboxybetaines 1 and 2 was 5% or less, but the increase in yield for carboxybetaines 3 to 5 was 10% or more.

[0089] [Table 20]

[0090] Example 12: Effect of different concentrations of carboxybetaine 5 on the yield of Suzuki-Miyaura coupling reaction The Suzuki-Miyaura coupling reaction was carried out in the same manner as in Example 1 by changing the concentration of the aqueous solution of carboxybetaine 5 used as the reaction solvent in the range of 0 M to 2.0 M, and the reaction yield was calculated.

[0091] The results are shown in Table 21. The reaction yield in the aqueous solution of carboxybetaine 5 varied depending on the concentration of carboxybetaine 5. The yield increased by 32% in an aqueous solution containing carboxybetaine 5 at a concentration of 0.10M, 36% at 0.25M, 52% at 0.50M, 52% at 1.00M, and 25% at 2.00M. There was a difference depending on the concentration of carboxybetaine, and under these reaction conditions (60°C, 1 hour), the yield was maximum when the concentration of carboxybetaine 5 was 0.50 to 1.00M. However, it was confirmed that the yield increased further when the reaction time was changed (63% at 1 hour of reaction time, 78% at 21 hours of reaction time), and it is considered that the concentration of carboxybetaine 5 affects the reaction rate rather than the yield. That is, in Example 11, the yield of carboxybetaine 5 was lower than that of carboxybetaine 4, but when the concentration of carboxybetaine 5 was in the range of 0.50 M to 1.00 M, the yield was equivalent to that of carboxybetaine 4. Therefore, it is considered that carboxybetaine 4 and carboxybetaine 5 have equivalent abilities if the concentrations used are appropriately selected.

[0092] [Table 21]

[0093] Comparative Example 1: Comparison of yields in Suzuki-Miyaura coupling reaction when an aqueous surfactant solution is used as the reaction solvent It has been reported that surfactants are used to carry out chemical reactions in water. It is considered that it is good for large micelles to form in reactions using surfactants, and TPGS-750-M and NOK are the most suitable surfactants for forming such micelles (see Non-Patent Documents 2 and 3). The optimal concentration of these surfactants has been reported to be 2 wt%, and in this experiment, carboxybetaine 5, TPGS-750-M (Sigma-Aldrich, model number 763896-1G), and 2 wt% NOK aqueous solution (Sigma-Aldrich, model number 776033-50ML) were diluted to 2 wt% to prepare aqueous solutions, which were used as reaction solvents. The Suzuki-Miyaura coupling reaction was used as the reaction, and the reaction conditions were changed to 60°C and 4 hours, and the Suzuki-Miyaura coupling reaction was carried out in the same manner as in Example 1, and the reaction yield was calculated.

[0094] The results are shown in Table 22. It was revealed that the reaction in an aqueous solution of carboxybetaine 5 resulted in a yield 9 to 20% higher than that in TPGS-750-M and NOK, which are reported to be effective surfactants. In other words, this shows that the reaction in an aqueous solution containing carboxybetaine represented by general formula (1) results in a higher yield than that in aqueous solutions of existing surfactants.

[0095] [Table 22]

[0096] In addition, when observing the state of the reaction solution during the reaction, it was found that there was a big difference between surfactants and betaine. Figure 1 shows photographs of the solution during the reaction. The foaming characteristic of surfactants can be seen in the aqueous solutions containing TPGS-750-M and NOK. In particular, it was confirmed that bubbles with a volume four times that of the solution were generated with NOK, and bubbles with a volume twice that of the solution were generated with TPGS-750-M. On the other hand, almost no foam was observed in the aqueous solution containing betaine 5. When synthesizing on a large scale, the volume of the bubbles affects the size of the reaction vessel, so in this respect too, the aqueous solution containing betaine 5 can be said to be superior to the aqueous solution containing a surfactant.

Claims

1. A reaction solvent for organic chemical reactions (excluding reaction solvents used in reactions using lipase substrates or leuco chromogens), comprising an aqueous solution containing a carboxybetaine represented by the following general formula (1): 【Chemistry 1】 [In the general formula (1), R 1 , R 2 , and R 3 each represents an alkyl group having 3 to 5 carbon atoms, which may be the same or different, and R 1 , R 2 , and R 3 The total number of carbon atoms in the alkyl groups of R is 9 to 15. 4 is a methylene group.

2. In the general formula (1), R 1 , R 2 , and R 3 is an alkyl group having 4 or 5 carbon atoms, and R 4 The reaction solvent according to claim 1 , wherein is a methylene group.

3. The reaction solvent according to claim 1 or 2, wherein the concentration of the carboxybetaine represented by the general formula (1) in the aqueous solution is 0.01 to 3 M.

4. A method for carrying out an organic chemical reaction (excluding reactions using a lipase substrate or a leuco chromogen) using the reaction solvent according to any one of claims 1 to 3.

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