JP7617556B2 - Aqueous reaction solvents used in organic chemical reactions - Google Patents

Description

The present invention relates to an aqueous reaction solvent that can efficiently carry out an organic chemical reaction. The present invention also relates to a method for carrying out an organic chemical reaction using the aqueous reaction solvent.

Traditionally, 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 it were possible to replace the organic solvents used in organic chemical reactions with water, it is expected that there would be positive effects in terms of the environment and the economy.

On the other hand, water is an attractive solvent because of its characteristics such as low cost, nonflammability, nontoxicity, and environmental compatibility, but it has difficulties in terms of solubility of substrates and reactivity in organic chemical reactions, and is therefore very 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.

In light of the current state of the art, there is a strong need to develop aqueous reaction solvents that can efficiently carry out organic chemical reactions.

Kevin H. Shaughnessy et al. , Current Organic Chemistry, 2005, 9, 585-604 B. H. Lipshutz et al. , J. Org. Chem. , 2011, 76, 4379-4391 P. Klumphu, B. H. , Lipshutz, J. Org. Chem. , 2014, 79, 888-900

The object of the present invention is to provide an aqueous reaction solvent that can efficiently carry out organic chemical reactions.

The inventors conducted extensive research to solve the above problems and discovered that the reaction efficiency of organic chemical reactions can be improved by using an aqueous solution containing a carboxybetaine of a specific structure as a reaction solvent. The present invention was completed based on this knowledge and through further research.

［一般式（１）において、Ｒ₁、Ｒ₂、及びＲ₃は、それぞれ同一又は異なるアルキル基を示し、且つＲ₁、Ｒ₂、及びＲ₃のアルキル基の合計炭素数が９～１５であり、Ｒ₄は、炭素数１～５のアルキレン基である。］
項２． 前記一般式（１）において、Ｒ₁、Ｒ₂、及びＲ₃が、それぞれ同一又は異なって、炭素数３～５のアルキル基であり、且つＲ₄がメチレン基である、項１に記載の反応溶媒。
項３． 前記一般式（１）において、Ｒ₁、Ｒ₂、及びＲ₃が、炭素数４又は５のアルキル基であり、且つＲ₄がメチレン基である、項１又は２に記載の反応溶媒。
項４． 水溶液中での一般式（１）で示されるカルボキシベタインの濃度が０.０１～３Ｍである、項１～３のいずれかに記載の反応溶媒。
項５． 項１～４のいずれかに記載の反応溶媒を用いて有機化学反応を行う、有機化学反応方法。 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):

[In the general formula (1), R ₁ , R ₂ , and R ₃ each represent the same or different alkyl group, the total number of carbon atoms of the alkyl groups of R ₁ , R ₂ , and R ₃ is 9 to 15, and R ₄ is an alkylene group having 1 to 5 carbon atoms.]
Item 2. The reaction solvent according to Item 1, wherein, 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. The reaction solvent according to item 1 or 2, wherein in the general formula (1), R ₁ , R ₂ , and R ₃ are alkyl groups having 4 or 5 carbon atoms, and R ₄ 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. An organic chemical reaction method, comprising carrying out an organic chemical reaction using the reaction solvent according to any one of Items 1 to 4.

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

This is a photographic image showing the appearance during the Suzuki-Miyaura coupling reaction using a 2 wt % aqueous solution of betaine 5, a 2 wt % aqueous solution of TPGS-750-M, and a 2 wt % aqueous solution of NOK as reaction solvents.

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

[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.

In the general formula (1), R ₁ , R ₂ , and R ₃ each represent the same or different alkyl group, and the total number of carbon atoms of the alkyl groups of R ₁ , R ₂ , and R ₃ is 9 to 15. In the present invention, the "total number of carbon atoms of the alkyl groups of R ₁ , R ₂ , and R ₃ " is the total value of the carbon number of the alkyl group of R ₁ , the carbon number of the alkyl group of R ₂ , and the carbon number of the alkyl group of R _3. By using a carboxybetaine in which the total number of carbon atoms of the alkyl groups of _{R 1} , R ₂ , and R ₃ falls within the above range, it is possible to improve the reaction efficiency of an organic chemical reaction. From the viewpoint of further improving the reaction efficiency of an organic chemical reaction, the total number of carbon atoms of the alkyl groups of R ₁ , R ₂ , and R ₃ is preferably 10 to 15, more preferably 11 to 15, even more preferably 12 to 15, and even more preferably 12 or 15.

The number of carbon atoms in each of the alkyl groups R ₁ , R ₂ , and R ₃ is not particularly limited as long as the total number of carbon atoms falls within the above-mentioned range, and examples thereof include 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.

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

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

Preferred examples of carboxybetaines represented by general formula (1) include compounds in which 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 in general formula (1); and more preferred compounds in which 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 in general formula (1).

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

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

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, even more preferably 0.25 to 1 M, and particularly preferably 0.5 to 1 M.

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 surfactants, if necessary, as long as the effects of the present invention are not lost.

[Uses of reaction solvents]
The reaction solvent of the present invention is not particularly limited in 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 (alkene, primary hydroxyl group, 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 (nitrile, amide, ester, thioester, glycoside, ether, acetal, ketal, carbamate, phosphate ester 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-Beachel rearrangement, Smiles rearrangement, Fries rearrangement, Beckmann rearrangement, Curtius rearrangement, Rossen rearrangement, Hoffmann rearrangement, Schmidt reaction, Baeyer-Williger 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, halohydrin reaction, Grignard reaction, aldol condensation, Mukaiyama aldol condensation, Claisen condensation, benzoin condensation, Dieckmann condensation, Stobbe condensation , Crane-Ke 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 reactions (Sharpless asymmetric amination, Jacobsen-Katsuki asymmetric epoxidation, Rausch asymmetric allylation, etc.), polymerization reactions (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.

These chemical reactions are well known, and a person skilled in the art would be able to understand the reaction mechanisms of these chemical reactions based on well-known techniques.

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

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

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.

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

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 an acid anhydride with the aromatic ring compound in the presence of a Lewis acid.

A hydride reduction reaction is a chemical reaction in which a compound is reduced using a hydrogen donor as a nucleophile.

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 that has a leaving group, such as a halide or sulfonate, in the presence of a strong base.

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

Among hydrolysis reactions, for example, the hydrolysis of nitriles is a chemical reaction that converts the cyano group of a compound having a cyano group into an amide group or a carboxyl group in the presence of an acid or a base.

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, monocyclic compounds, and polycyclic compounds.

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

2. Organic Chemical Reaction Method 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, the substrate to be used, etc. in the organic chemical reaction method of the present invention are as described in the above section "1. Reaction Solvent".

The present invention will be specifically explained below with reference to examples, but the present invention is not limited to these in any way.

Production Example: Production of various carboxybetaines The following carboxybetaines 1 to 5 were synthesized with reference to the method described in JP 2009-96766 A. Carboxybetaine 1 is a compound in which R ₁ to R ₃ are methyl groups and R ₄ is a methylene group in the general formula (1), Carboxybetaine 2 is a compound in which R ₁ to R ₃ are ethyl groups and R ₄ is a methylene group in the general formula (1), Carboxybetaine 3 is a compound in which R ₁ to R ₃ are propyl groups and R ₄ is a methylene group in the general formula (1), Carboxybetaine 4 is a compound in which R ₁ to R ₃ are butyl groups and R ₄ is a methylene group in the general formula (1), and Carboxybetaine 5 is a compound in which R ₁ to R ₃ are pentyl groups and R ₄ is a methylene group in the general formula (1).

Example 1 Suzuki-Miyaura Coupling Reaction in Aqueous Solution of Carboxybetaine 5 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 No. 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 No. T1951-5G), and Pd( _PPh3 ) ₄ (Colonial To the mixture, 14.4 mg (0.0125 mmol, 0.7 mol%) of potassium carbonate (Fujifilm Wako Pure Chemical Industries, Ltd., model number 5094), 173.3 mg (1.25 mmol), 1.5 ml of 2.0 M carboxybetaine 5 aqueous solution or 1.5 ml of distilled water 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 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 (Fuji Silysia, Ltd., model number PSQ100AB)), chloroform (Fujifilm Wako Pure Chemical Industries, Ltd., model number 033-02617):hexane (Fujifilm Wako Pure Chemical Industries, Ltd., model number 080-00427) = 2:1), and dried under reduced pressure to obtain a reddish brown solid.

The product (reddish brown solid) was identified by ¹ H NMR, and it was confirmed that a product having the desired structure was obtained (Table 1).

The yield and yield of the product 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%, a 25% increase in yield when using an aqueous solution of carboxybetaine 5 compared to distilled water.

Example 2: Acetylation reaction of 1-naphthol in an aqueous solution of carboxybetaine 5 14.4 mg (0.1 mmol) of 1-naphthol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., model number 148-00215), 94.5 μl (1 mmol) of acetic anhydride (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., model number 017-00273), 1.0 ml of a 2.0 M aqueous solution of carboxybetaine 5, 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 60° C. for 20 hours to carry out an acetylation reaction of 1-naphthol. After allowing the reaction solution 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.

The product (white solid) was identified by ¹ H NMR, and it was confirmed that the product had the desired structure (Table 3).

The yield and yield of the product are shown in Table 4. When the acetylation reaction of 1-naphthol was carried out in distilled water, the reaction did not proceed at all, whereas when the acetylation reaction of 1-naphthol was carried out in an aqueous solution of carboxybetaine 5, the yield was 83%, and the yield was significantly higher in the aqueous solution of carboxybetaine 5 compared to distilled water.

Example 3: Aromatic bromination reaction in an aqueous solution of carboxybetaine 5 14.4 mg (0.1 mmol) of 1-naphthol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., model number 148-00215), 17.8 mg (0.1 mmol) of N-bromosuccinimide (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., model number 025-07235), 1.0 ml of a 2.0 M aqueous solution of carboxybetaine 5 or 1.00 ml of distilled water were added to a 10 mL screw-cap test tube, and the mixture was 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.

The product (yellow solid) was identified by ¹ H NMR, and it was confirmed that the product had the desired structure (Table 5).

The yield and yield of the product are shown in Table 6. When 1-naphthol was brominated in distilled water, the yield was 19%, whereas when 1-naphthol was brominated in an aqueous solution of carboxybetaine 5, the yield was 31%, meaning that the yield was increased by 12% when using an aqueous solution of carboxybetaine 5 compared to distilled water.

Example 4: Reduction reaction of aldehyde in aqueous solution of carboxybetaine 5 18.5 mg (0.1 mmol) of o-bromobenzaldehyde (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., model number 020-13172), 37.8 mg (0.1 mmol) of _NaBH4 (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., model number 192-01472), 1.0 ml of 2.0 M aqueous solution of carboxybetaine 5 or 1.0 ml of distilled water were added to a 10 mL screw-cap test tube and stirred for 3 hours at 30° C. to carry out the reduction reaction of aldehyde. After completion of the reaction, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography (silica gel, chloroform:methanol (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., model number 136-01837) = 20:1), and dried under reduced pressure to obtain a white solid.

The product (white solid) was identified by ¹ H NMR, and it was confirmed that a product having the desired structure was obtained (Table 7).

The yield and yield of the product 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 an aqueous solution of carboxybetaine 5 compared to distilled water.

Example 5: Aromatic Friedel-Crafts acylation reaction in carboxybetaine 5 aqueous solution To a 10 mL screw-cap test tube, 10.6 μl (0.1 mmol) of toluene (FUJIFILM Wako Pure Chemical Industries, Ltd., model number 204-01866), 13.3 mg (0.1 mmol) of AlCl ₃ (FUJIFILM Wako Pure Chemical Industries, Ltd., model number 013-01892), 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 a Friedel-Crafts acylation reaction. After allowing the reaction solution 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.

The product (white solid) was identified by ¹ H NMR, and it was confirmed that the product had the desired structure (Table 9).

The yield and yield of the product are shown in Table 10. When the Friedel-Crafts acylation reaction was carried out in distilled water, the reaction did not proceed at all, whereas when the Friedel-Crafts acylation reaction was carried out in an aqueous solution of carboxybetaine 5, the yield was 14%, and the yield was significantly higher in the aqueous solution of carboxybetaine 5 compared to distilled water.

Example 6 Williamson ether synthesis reaction in carboxybetaine aqueous 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 a 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.

The product (white solid) was identified by ¹ H NMR, and it was confirmed that a product having the desired structure was obtained (Table 11).

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%, and the yield was increased by 88% when using an aqueous solution of carboxybetaine 5 compared to distilled water.

Example 7: N-alkylation reaction in an aqueous solution of carboxybetaine 5 36.5 μl (0.4 mmol) of aniline (Tokyo Chemical Industry Co., Ltd., model number A0463-500G), 12.7 mg (0.1 mmol) of benzyl chloride (Fujifilm Wako Pure Chemical Industries, Ltd., model number 020-01386), 1.0 ml of a 2.0 M aqueous solution of carboxybetaine 5 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 4 hours to carry out an N-alkylation reaction of aniline. After allowing the reaction solution 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.

The product (white solid) was identified by ¹ H NMR, and it was confirmed that the product had the desired structure (Table 13).

The yield and yield of the product are shown in Table 14. When the N-alkylation reaction of aniline was carried out in distilled water, the yield was 24%, whereas when the N-alkylation reaction of aniline was carried out in an aqueous solution of carboxybetaine 5, the yield was 46%, meaning that the yield was increased by 22% when using an aqueous solution of carboxybetaine 5 compared to distilled water.

Example 8: Wittig reaction in carboxybetaine 5 aqueous solution 43.9 mg (0.1 mmol) of (1-naphthylmethyl)triphenylphosphonium chloride (Tokyo Chemical Industry Co., Ltd., model number N0700-5G), 10.2 μl (0.1 mmol) of benzaldehyde (Fujifilm Wako Pure Chemical Industries, Ltd., model number 025-12206), 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-cap test tube, and the mixture was heated and stirred at 60° C. for 4 hours to carry out a 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.

The product (white solid) was identified by ¹ H NMR, and it was confirmed that the product had the desired structure (Table 15).

The yield and yield of the product are shown in Table 16. When the Wittig reaction was carried out in distilled water, the yield was 29%, whereas when the Wittig reaction was carried out in an aqueous solution of carboxybetaine 5, the yield was 55%, meaning that the yield was increased by 26% when using an aqueous solution of carboxybetaine 5 compared to distilled water.

Example 9: Hydrolysis reaction of nitrile in aqueous solution of carboxybetaine 5 11.8 mg (0.1 mmol) of 4-aminobenzonitrile (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., model number 014-10651), 40.0 mg (1 mmol) of NaOH (manufactured by Fujifilm Wako Pure Chemical Industries, Ltd., model number 198-13765), 1.0 ml of 2.0 M aqueous solution of betaine 5 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 60° C. for 4 hours to carry out 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.

The product (white solid) was identified by ¹ H NMR, and it was confirmed that the product had the desired structure (Table 17).

The yield and yield of the product 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%, and the yield was increased by 78% when using an aqueous solution of carboxybetaine 5 compared to distilled water.

[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.

Example 10: Effect of raw material substrates used in Suzuki-Miyaura coupling reaction on yield In order to consider the effect 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.

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 reactions using an aqueous solution of carboxybetaine 5 as the solvent was not affected by the structure of the raw substrate.

Example 11: Effect of difference in chemical structure of carboxybetaine on yield of 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.

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 less than 5%, but the increase in yield for carboxybetaines 3 to 5 was more than 10%.

Example 12: Effect of difference in concentration 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, except that the concentration of the aqueous carboxybetaine 5 solution used as the reaction solvent was changed in the range from 0 M to 2.0 M, and the reaction yield was calculated.

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 0.10 M, 36% at 0.25 M, 52% at 0.50 M, 52% at 1.00 M, and 25% at 2.00 M. There were differences 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 1.00 M. However, it was confirmed that the yield increased further when the reaction time was changed (63% at 1 hour reaction time, 78% at 21 hours reaction time), and it is thought 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 if the concentration of carboxybetaine 5 was in the range of 0.50M to 1.00M, the yield was equivalent to that of carboxybetaine 4. Therefore, if the concentration used is appropriately selected, it is believed that carboxybetaine 4 and carboxybetaine 5 have equivalent capabilities.

Comparative Example 1: Comparison of yields in Suzuki-Miyaura coupling reaction with a case where a surfactant aqueous solution is used as a 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 a reaction using a surfactant to form large micelles, and TPGS-750-M and NOK are optimal 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, aqueous solutions of carboxybetaine 5, TPGS-750-M (Sigma-Aldrich, model number 763896-1G), and 2 wt% NOK aqueous solution (Sigma-Aldrich, model number 776033-50ML) diluted to 2 wt% were prepared and 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.

The results are shown in Table 22. It was found that the reaction in an aqueous solution of carboxybetaine 5 resulted in a yield 9 to 20% higher than that of 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 shown in general formula (1) results in a higher yield than that of existing aqueous solutions of surfactants.

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 a photograph 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 in the case of NOK, and bubbles with a volume twice that of the solution were generated in the case of TPGS-750-M. On the other hand, almost no bubbles were 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, it can be said that an aqueous solution containing betaine 5 shows an advantage over the use of an aqueous solution containing a surfactant.

Claims (4)

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):
[In the general formula (1), R ₁ , R ₂ , and R ₃ are each the same or different alkyl groups having 3 to 5 carbon atoms , the total number of carbon atoms of the alkyl groups of R ₁ , R ₂ , and R ₃ is 9 to 15, and R ₄ is a methylene group .] 2. The reaction solvent according to claim 1 , wherein in said general formula (1), R ₁ , R ₂ and R ₃ are alkyl groups having 4 or 5 carbon atoms, and R ₄ is a methylene group. 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. 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 .