Method for producing carboxylic acid ester

Abstract

To provide a method for producing a carboxylic acid ester using 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM), which enables the formation of high-purity, high-yield products with high substrate generality by resolving the constraint that production has been limited to specific conditions.SOLUTION: The present invention provides a method for producing a carboxylic acid ester by condensing a carboxylic acid and an alcohol in the presence of DMT-MM, wherein the reaction temperature is maintained at 15°C or less for at least the first 15 minutes after the reaction initiation, and 4-(dimethylamino)pyridine is added in an amount of 0.01 to 0.5 mol per 1 mol of DMT-MM.SELECTED DRAWING: None

Description

[Technical field]

[0001] The present invention relates to a method for producing a carboxylic acid ester. [Background technology]

[0002] 4-(4,6-Dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (hereinafter referred to as DMT-MM) is a dehydration condensation type amidation / esterification agent (Patent Document 1). When DMT-MM is applied to amidation, the reaction proceeds even in water or alcohol, so it is widely used. On the other hand, there are few reports of its use as an esterification agent, and only Patent Document 1 and Non-Patent Documents 1 to 3 have been found. [Prior art documents] [Patent documents]

[0003] [Patent Document 1] JP 2001-247555 A [Non-patent literature]

[0004] [Non-Patent Document 1] Kunishima M., Kawachi C., Monta J., Terao K., Iwasaki F., Tani S., Tetrahedron,1999,55,13159-13170. [Non-Patent Document 2] Kunishima M., Monta J., Kawachi C., Iwasaki F., Terao K., Tani S., Synlett, 1999, 1255-1256. [Non-Patent Document 3] Baran PS, Li K., O'Malley DP, Mitsos C., Angew. Chem. Int. Ed., 2005, 45, 249-252. Summary of the Invention [Problem to be solved by the invention]

[0005] In the examples of Patent Document 1, and Non-Patent Documents 1 and 2, a carboxylic acid and a solvent amount of alcohol are used, and the reaction is carried out in the presence of DMT-MM and N-methylmorpholine, and the yield and purity are not fully satisfactory. In Non-Patent Document 3, a carboxylic acid and a solvent amount of alcohol are used, heated to 50° C., and reacted in the presence of DMT-MM and 4-(dimethylamino)pyridine (hereinafter referred to as DMAP), but the substrate generality is low, and when applied to other substrates, the yield is low and is not satisfactory. That is, the conventional method for producing carboxylic acid esters using DMT-MM as a condensing agent has problems such as (1) the use of a large amount of solvent because alcohols are less reactive with carboxylic acids than amines, and (2) DMT-MM is unstable in many organic solvents, and the quaternary ammonium group decomposes and no longer functions as a dehydration condensing agent. Therefore, the few reported examples mentioned above were limited to cases where the alcohol constituting the target ester was used as the solvent or where a highly reactive carboxylic acid was used.

[0006] Therefore, an object of the present invention is to solve the problem that in the method for producing carboxylic acid esters using DMT-MM, the production has only been possible under limited conditions, and to provide a production method with high substrate generality, high purity, and high yield. [Means for solving the problem]

[0007] As a result of intensive research aimed at solving the above-mentioned problems, the present inventors have found that by allowing DMT-MM and a small amount of DMAP to coexist with a carboxylic acid and an alcohol and by keeping the initial reaction temperature low to suppress decomposition of DMT-MM, a high-purity carboxylic acid ester can be produced in high yield under mild conditions without using an excess of alcohol, and have completed the present invention.

[0008] That is, the present invention provides the following inventions [1] to [7]. [1] A method for producing a carboxylic acid ester by condensing a carboxylic acid with an alcohol in the presence of DMT-MM, comprising the steps of: A method for producing a carboxylic acid ester, comprising maintaining a reaction temperature at 15° C. or lower for at least 15 minutes after the start of the reaction and adding 0.01 to 0.5 mol of DMAP per mol of DMT-MM. [2] The method of producing the present invention described in [1], wherein the reaction temperature is 20°C or higher 15 minutes after the start of the reaction. [3] The method according to [1] or [2], wherein DMAP is added at least 15 minutes after the start of the reaction. [4] The method according to any one of [1] to [3], wherein the reaction is carried out in an aprotic solvent. [5] The method according to any one of [1] to [4], wherein the amount of DMT-MM used is 1 to 1.5 moles per mole of carboxylic acid. [6] The method according to any one of [1] to [5], wherein the reaction temperature is 10° C. or lower for at least 15 minutes after the start of the reaction. [7] The method according to any one of [1] to [6], further comprising adding 0.01 to 0.5 mol of an organic base or an inorganic base other than DMAP per 1 mol of DMT-MM. Effect of the Invention

[0009] According to the method of the present invention, it is possible to produce a high-purity carboxylic acid ester in high yield under mild conditions without using a large amount of alcohol, while suppressing the decomposition of the condensation agent DMT-MM and thereby suppressing the occurrence of side reactions. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0010] Terms used in this specification are used in the same manner as commonly used in the art unless otherwise specified.

[0011] In this specification, a carboxylic acid is an organic acid having at least one carboxy group (-COOH). Specifically, the carboxylic acid is represented by the following general formula (1):

[0012] [ka]

[0013] (In the formula, R 1 represents a hydrogen atom or an organic group. It is a compound represented by the formula:

[0014] In the present invention, R 1 is preferably a hydrogen atom, a linear alkyl group having 1 to 36 carbon atoms, an alkenyl group, alkynyl group, alkylamide group, alkyl ester group or alkyl ether group having 2 to 36 carbon atoms, a branched or cyclic hydrocarbon group having 3 to 36 carbon atoms, an aromatic hydrocarbon group having 6 to 36 carbon atoms, a saturated or unsaturated heterocyclic group, or a combination thereof.

[0015] In this specification, alcohol is a general term for a substance in which the hydrogen atom of a hydrocarbon is replaced with a hydroxyl group (-OH). Specifically, the alcohol is represented by the following general formula (2):

[0016] [ka]

[0017] (In the formula, R 2 indicates an organic group) It is a compound represented by the formula:

[0018] In the present invention, R 2 As the alkyl group, a linear alkyl group having 1 to 36 carbon atoms, an alkenyl group, alkynyl group, alkylamide group, alkyl ester group or alkyl ether group having 2 to 36 carbon atoms, a branched or cyclic hydrocarbon group having 3 to 36 carbon atoms, an aromatic hydrocarbon group having 6 to 36 carbon atoms, a saturated or unsaturated heterocyclic group, or a combination thereof is preferable.

[0019] In this specification, the term "carboxylate" refers to a compound obtained by dehydration condensation of a carboxy group of a carboxylic acid and a hydroxy group of an alcohol. Specifically, the compound represented by the following general formula (3)

[0020] [ka]

[0021] (In the formula, R 1 represents a hydrogen atom or an organic group, R 2 indicates an organic group) It is a compound represented by the formula:

[0022] In the present invention, R 1 is preferably a hydrogen atom, a linear alkyl group having 1 to 36 carbon atoms, an alkenyl group, an alkynyl group, an alkylamide group, an alkyl ester group, or an alkyl ether group having 2 to 36 carbon atoms, a branched or cyclic hydrocarbon group having 3 to 36 carbon atoms, an aromatic hydrocarbon group having 6 to 36 carbon atoms, a saturated or unsaturated heterocyclic group, or a combination of these. 2 As the alkyl group, a linear alkyl group having 1 to 36 carbon atoms, an alkenyl group, alkynyl group, alkylamide group, alkyl ester group or alkyl ether group having 2 to 36 carbon atoms, a branched or cyclic hydrocarbon group having 3 to 36 carbon atoms, an aromatic hydrocarbon group having 6 to 36 carbon atoms, a saturated or unsaturated heterocyclic group, or a combination thereof is preferable.

[0023] In this specification, the condensation agent refers to a reaction reagent for one-pot synthesis of carboxylic acid derivatives such as esters and amides by addition-elimination reaction. In the present invention, the above-mentioned DMT-MM is used as a dehydration condensation agent. The chemical formula of DMT-MM is shown below.

[0024] [ka]

[0025] In this specification, a base refers to a chemical species that accepts a proton or donates an electron pair. There are organic bases and inorganic bases, and the organic base in the present invention is a Brönsted base that accepts a proton. Many of the compounds used as organic bases are amines or heterocyclic compounds containing a nitrogen atom, which easily accept a proton on the nitrogen atom to become a cation (conjugate acid) such as ammonium. Examples of the organic base used in the present invention include alkylamines such as ethylamine and 1-propylamine, dialkylamines such as dimethylamine and diethylamine, trialkylamines such as triethylamine and diisopropylethylamine, cyclic amines such as piperidine, pyrrolidine and N-methylmorpholine, and anilines such as dimethylaniline. The inorganic base used in the present invention includes alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkali metal hydrogen carbonates, metal hydrides, and the like.

[0026] One aspect of the present invention is a method for producing a carboxylic acid ester by condensing a carboxylic acid and an alcohol in the presence of DMT-MM, characterized in that the reaction temperature is kept at 15°C or lower for at least 15 minutes after the start of the reaction, and DMAP is added in an amount of 0.01 to 0.5 mol per mol of DMT-MM.

[0027] The carboxylic acid used as the raw material may be a compound represented by the general formula (1). 1 is preferably a hydrogen atom, a linear alkyl group having 1 to 36 carbon atoms, an alkenyl group, alkynyl group, alkylamide group, alkyl ester group or alkyl ether group having 2 to 36 carbon atoms, a branched or cyclic hydrocarbon group having 3 to 36 carbon atoms, an aromatic hydrocarbon group having 6 to 36 carbon atoms, a saturated or unsaturated heterocyclic group, or a combination thereof.

[0028] The alcohol used as the other raw material may be a compound represented by the general formula (2). 2As the alkyl group, a linear alkyl group having 1 to 36 carbon atoms, an alkenyl group, alkynyl group, alkylamide group, alkyl ester group or alkyl ether group having 2 to 36 carbon atoms, a branched or cyclic hydrocarbon group having 3 to 36 carbon atoms, an aromatic hydrocarbon group having 6 to 36 carbon atoms, a saturated or unsaturated heterocyclic group, or a combination thereof is preferable.

[0029] In the present invention, the amount of alcohol used is preferably about 1 mol to 1.5 mol, more preferably 1 mol to 1.2 mol, and even more preferably 1 mol to 1.1 mol, per mol of carboxylic acid. There is no need to use a large excess of alcohol as in the conventional method.

[0030] In the present invention, DMT-MM is used as a condensation agent. As described in Patent Document 1, DMT-MM may contain a certain amount of water. The amount of DMT-MM used is not particularly limited, but from the viewpoints of preventing side reactions and increasing the yield and purity of the carboxylic acid ester, it is preferably 1 mol to 1.5 mol, more preferably 1 mol to 1.3 mol, and even more preferably 1 mol to 1.2 mol, per 1 mol of carboxylic acid.

[0031] In the present invention, the reaction temperature at the beginning of the reaction is important from the viewpoint of preventing decomposition of the condensing agent DMT-MM and preventing side reactions. That is, by setting the reaction temperature of the reaction solution containing carboxylic acid, alcohol, and DMT-MM to 15° C. or less for at least 15 minutes from the start of the reaction, decomposition of DMT-MM can be prevented. More preferably, the reaction temperature for at least 15 minutes from the start of the reaction is set to 10° C. or less, and even more preferably 5° C. or less. The time for keeping the reaction temperature at 15° C. or less may be at least 15 minutes from the start of the reaction, but is more preferably at least 20 minutes, and even more preferably at least 30 minutes. After such temperature control at the beginning of the reaction, i.e., 15 to 30 minutes after the start of the reaction, the reaction temperature may be 20°C or higher, more preferably 20°C to 50°C, and even more preferably 25°C to 35°C.

[0032] In the present invention, it is preferable to add 0.01 to 0.5 mol of DMAP, which is a type of organic base, per 1 mol of DMT-MM, in order to suppress decomposition of DMT-MM and improve the yield and purity of the carboxylate. DMAP may be used from the early stage of the reaction, but it is preferable to add it to the reaction system after 15 to 30 minutes from the early stage of the reaction in order to prevent the reaction between DMT-MM and DMAP and to prevent the inactivation of DMT-MM. Alternatively, half of the total amount of DMAP may be added at the early stage of the reaction, and the remaining half may be added after the early stage of the reaction.

[0033] In the present invention, in order to make the reaction proceed more rapidly, an organic base or an inorganic base other than DMAP may be further used. Examples of the organic base to be used include alkylamines such as ethylamine and 1-propylamine, dialkylamines such as dimethylamine and diethylamine, trialkylamines such as triethylamine and diisopropylethylamine, cyclic amines such as piperidine, pyrrolidine and N-methylmorpholine, and anilines such as dimethylaniline. The inorganic base to be used includes alkali metal hydroxides, alkaline earth metal hydroxides, alkali metal carbonates, alkali metal hydrogen carbonates, metal hydrides, and the like. The amount of these organic or inorganic bases other than DMAP used is preferably 0.05 to 2 moles, and more preferably 0.1 to 2 moles, per mole of carboxylic acid.

[0034] In the method of the present invention, it is not necessary to use an excess amount of alcohol as a reaction solvent, and an aprotic solvent can be used as the reaction solvent.Specific examples of the reaction solvent include ethers such as tetrahydrofuran, 1,4-dioxane, diethyl ether, and diisopropyl ether, halogenated aliphatic hydrocarbons such as dichloromethane, chloroform, and carbon tetrachloride, ketones such as acetone, methyl ethyl ketone, and methyl isobutyl ketone, nitriles such as acetonitrile and propionitrile, aromatic hydrocarbons such as benzene, toluene, and xylene, halogenated aromatic hydrocarbons such as chlorobenzene and dichlorobenzene, amides such as N,N-dimethylformamide and N,N-dimethylacetamide, aliphatic hydrocarbons such as hexane and heptane, and dimethyl sulfoxide.

[0035] In the present invention, the reaction is carried out at a low temperature in the early stage and then at a temperature of 20° C. or higher, and a total reaction time of 1 to 30 hours is sufficient.

[0036] In conventional methods, decomposition products of DMT-MM are produced as by-products, and therefore purification by silica gel column chromatography or the like is required after completion of the reaction. However, in the method of the present invention, the reaction between DMT-MM and other components is suppressed, making it possible to purify the reaction solution simply by separating it with an acidic aqueous solution. The acidic aqueous solution used for separation and washing can be an inorganic acid aqueous solution such as 10% or more hydrochloric acid, sulfuric acid aqueous solution, phosphoric acid aqueous solution, etc.

[0037] According to the method of the present invention, in a method for producing a carboxylic acid ester by condensing a carboxylic acid and an alcohol in the presence of DMT-MM, the reaction temperature at the initial stage of the reaction is kept low and the amount of DMAP added as an organic base is reduced, thereby suppressing the reaction between DMT-MM and DMAP, etc. and side reactions accompanying this reaction, and thereby making it possible to produce a high-purity carboxylic acid ester in high yield under mild conditions. EXAMPLES

[0038] Next, examples will be given to more specifically explain the present invention, but the present invention is not limited to only the following examples.

[0039] (HPLC conditions) Column: InertSustain C18 HP, 4.6mm x 150mm, 3μm (GL Sciences) Column oven: 40℃ Wavelength: 220nm Flow rate: 1.5mL / min. Sample injection volume: 1μL

[0040] (Gradient conditions)

[0041] [Table 1]

[0042] (NMR analysis conditions) NMR was performed using a JNM-ECZ400S / L1 made by JEOL. The solvent used was deuterated chloroform. 1 H-NMR showed tetramethylsilane at 0.00 ppm, 13 The solvent peak was determined to be at 77.00 ppm in C-NMR.

[0043] Example 1

[0044] [ka]

[0045] [ka]

[0046] [ka]

[0047] In a 100mL test tube, 20.4g of dichloromethane (6.8wt times) and 3.0g of 3-phenylpropionic acid (20.0mmol) were taken and cooled to below 5℃. 0.20g of triethylamine (2.0mmol, 0.1mol times), 0.8g of methanol (24.0mmol, 1.2mol times) and 6.24g of DMT-MM (20.0mmol, 1.0mol times) were charged and stirred for 0.5 hours. After 0.5 hours, 0.24g of DMAP (2.0mmol, 10mol%) was added, and after aging at 5℃ or less for 1 hour, the temperature was raised to 30℃ and stirred at the same temperature for 2 hours. When analyzed by LC, the ratio of the raw material 3-phenylpropionic acid to the target methyl 3-phenylpropionate was 8.8:91.2, so the reaction was terminated. The reaction solution was cooled to below 5°C, and insoluble matter was removed by filtration. 20.4g of 50mM hydrochloric acid was added to the filtrate, and the liquids were separated. The organic layer was then washed with 20.4g of water, and washed twice with 20.4g of 10% aqueous potassium hydrogen carbonate solution. After further washing with 20.4g of water and 20.4g of 20% aqueous sodium chloride solution, the organic layer was dried over magnesium sulfate. The inorganic salts were filtered, and the filtrate was concentrated under reduced pressure with an evaporator at an external temperature of 30°C and 30mmHg. 2.9g of methyl 3-phenylpropionate was obtained as a colorless oily substance, with a yield of 88.7% and an LC purity of 94.9%. 1 When calculated by H-NMR, the pure yield was 2.8 g, and the yield was 86.7%. 1 H-NMR(400MHz, CDCl3):δ2.63(2H,t,J=7.8Hz,Ph-CH2-C H 2-C(=O)-O-),2.95(2H,t,J=7.8Hz,Ph-C H 2-CH2-), 3.66(3H,s,-C(=O)-OC H 3), 7.18-7.31(5H,m, Ph -CH2-); 13 C-NMR(100MHz,CDCl3):δ30.87(Ph- C H2-CH2-), 35.64(Ph-CH2- C H2-C(=O)-O-), 51.57(-C(=O)-O- C H3),126.21,128.21,128.45,140.44( Ph -CH2-), 173.29(-CH2- C (=O)-O-CH3).

[0048] [Table 2]

[0049] Example 2 The same procedure as in Example 1 was repeated except that 1.1 g (24.0 mmol, 1.2 mol times) of ethanol was used instead of methanol. 3.2 g of ethyl 3-phenylpropionate was obtained, with a yield of 89.9% and an LC purity of 92.0%. 1 When calculated by H-NMR, the pure yield was 3.1 g, and the yield was 86.7%. 1 H-NMR(400MHz, CDCl3):δ1.23(3H,t,J=7.1Hz,-C(=O)-O-CH2-C H 3), 2.61(2H,t,J=8.0Hz,Ph-CH2-C H 2-C(=O)-O-),2.95(2H,t,J=8.0Hz,Ph-C H 2-CH2-),4.12(2H,q,J=7.1Hz,-C(=O)-OC H 2-CH3), 7.18-7.31(5H,m, Ph -CH2-): 13 C-NMR(100MHz,CDCl3):δ14.13(-C(=O)-O-CH2- C H3), 30.90(Ph- C H2-CH2-), 35.87(Ph-CH2- C H2-C(=O)-O-), 60.33(-C(=O)-O- C H2-CH3),126.15,128.23,128.39,140.50( Ph -CH2-), 172.83(-CH2- C (=O)-O-CH2-).

[0050] Example 3 The same procedure as in Example 1 was repeated except that 1.4 g (24.0 mmol, 1.2 mol times) of 2-propanol was used instead of methanol. 2.6 g of 2-propyl 3-phenylpropionate was obtained, with a yield of 67.7% and an LC purity of 92.3%. 1 When calculated by H-NMR, the pure yield was 2.5 g, and the yield was 65.4%. 1 H-NMR(400MHz,CDCl3):δ1.20(6H,d,J=5.9Hz,-C(=O)-O-CH-(C H 3)2),2.59(2H,t,J=7.8Hz,Ph-CH2-C H 2-C(=O)-O-),2.94(2H,t,J=7.8Hz,Ph-C H 2-CH2-), 4.99(1H,m,-C(=O)-OC H -(CH3)2), 7.17-7.30(5H,m, Ph -CH2-): 13 C-NMR(100MHz,CDCl3):δ21.74(-C(=O)-O-CH-( C H3)2),30.97(Ph- C H2-CH2-), 36.17(Ph-CH2- C H2-C(=O)-O-), 67.61(-C(=O)-O- C H-(CH3)2),126.11,128.25,128.36,140.53( Ph -CH2-), 172.37(-CH2- C (=O)-O-CH<).

[0051] Example 4 The same procedure as in Example 1 was repeated except that 1.8 g (24.0 mmol, 1.2 mol times) of glycidol was used instead of methanol. 3.7 g of glycidyl 3-phenylpropionate was obtained, with a yield of 88.6% and an LC purity of 91.9%. 1 When calculated by H-NMR, the pure yield was 3.6 g, and the yield was 86.3%. 1 H-NMR(400MHz,CDCl3):δ2.59(1H,dd,J=2.4Hz,5.0Hz,-C(=O)-O-CH2-CH(-O-)-C HaHb),2.68(2H,t,J=7.8Hz,Ph-CH2-C H 2-C(=O)-O-),2.81(1H,dd,J=4.1Hz,5.0Hz,-C(=O)-O-CH2-CH(-O-)-CHa Hb ), 2.96(2H,t,J=7.8Hz,Ph-C H 2-CH2-),3.17(1H,m,-C(=O)-O-CH2-C H (-O-)-CH2),3.91(1H,dd,J=6.4Hz,12.4Hz,-C(=O)-OC Ha Hb-CH<),4.40(1H,dd,J=3.2Hz,12.4Hz,-C(=O)-O-CHa Hb -CH<), 7.18-7.32(5H,m, Ph -CH2-): 13 C-NMR(100MHz,CDCl3):δ30.74(Ph- C H2-CH2-), 35.53 (Ph-CH2- C H2-C(=O)-O-),44.52(-C(=O)-O-CH2-CH(-O-)- C H2), 49.19(-C(=O)-O-CH2- C H(-O-)-CH2), 64.86(-C(=O)-O- C H2-CH<),126.22,128.18,128.41,140.18( Ph -CH2-), 172.44(-CH2- C (=O)-O-CH2-).

[0052] Example 5 The same procedure as in Example 1 was repeated except that 1.4 g (24.0 mmol, 1.2 mol times) of allyl alcohol was used instead of methanol. 3.6 g of allyl 3-phenylpropionate was obtained, with a yield of 94.2% and an LC purity of 94.3%. 1 When calculated by H-NMR, the pure amount was 3.5 g, and the yield was 90.8%. 1 H-NMR(400MHz, CDCl3):δ2.66(2H,t,J=7.8Hz,Ph-CH2-C H 2-C(=O)-O-),2.96(2H,t,J=7.8Hz,Ph-CH 2-CH2-), 4.57(2H,m,-C(=O)-OC H 2-CH=CH2),5.21(1H,ddd,J=1.4Hz,2.7Hz,10.5Hz,-C(=O)-O-CH2-CH=C Ha Hb),5.28(1H,ddd,J=1.4Hz,3.2Hz,17.4Hz,-C(=O)-O-CH2-CH=CHa Hb ), 5.90(1H,m,-C(=O)-O-CH2-C H =CH2), 7.17-7.31(5H,m, Ph -CH2-): 13 C-NMR(100MHz,CDCl3):δ30.86(Ph- C H2-CH2-), 35.78(Ph-CH2- C H2-C(=O)-O-), 65.07(-C(=O)-O- C H2-CH=CH2),118.15(-C(=O)-O-CH2-CH= C H2),126.21,128.23,128.43,140.38( Ph -CH2-), 132.09(-C(=O)-O-CH2- C H=CH2), 172.45(-CH2- C (=O)-O-CH2-).

[0053] Example 6 The same procedure as in Example 1 was repeated except that 1.3 g (24.0 mmol, 1.2 mol times) of propargyl alcohol was used instead of methanol. 3.5 g of propargyl 3-phenylpropionate was obtained, with a yield of 92.0% and an LC purity of 94.1%. 1 When calculated by H-NMR, the pure yield was 3.4 g, and the yield was 90.8%. 1 H-NMR(400MHz,CDCl3):δ2.46(1H,t,J=2.5Hz,-C(=O)-O-CH2-C≡C H ), 2.67(2H,t,J=7.8Hz,Ph-CH2-C H 2-C(=O)-O-),2.96(2H,t,J=7.8Hz,Ph-C H2-CH2-),4.67(2H,d,J=2.5Hz,-C(=O)-OC H 2-C≡CH), 7.18-7.30(5H,m, Ph -CH2-): 13 C-NMR(100MHz, CDCl3):δ30.67(Ph- C H2-CH2-), 35.50 (Ph-CH2- C H2-C(=O)-O-), 51.86(-C(=O)-O- C H2-C≡CH),74.83(-C(=O)-O-CH2- C ≡CH),77.57(-C(=O)-O-CH2-C≡ C H),126.27,128.22,128.46,140.11( Ph -CH2-), 171.92(-CH2- C (=O)-O-CH2-).

[0054] Example 7

[0055] [ka]

[0056] 20.4g of dichloromethane (10wt times), 3.0g of 3-phenylpropionic acid (20.0mmol, 1.2mol times) were taken in a 100mL test tube and cooled to below 5℃. 0.28g of potassium carbonate (2.0mmol, 0.12mol times), 2.0g of 2-phenylethanol (16.7mmol), 6.24g of DMT-MM (20.0mmol, 1.2mol times) and 0.12g of DMAP (1.0 mol, 6mol%) were charged and stirred for 0.5 hours. After 0.5 hours, 0.12g of DMAP (1.0mmol, 6mol%) was added, and after aging at 5℃ or less for 1 hour, the temperature was raised to 30℃ and stirred at the same temperature for 20 hours. When analyzed by LC, the ratio of the raw material 2-phenylethanol to the target 3-phenylpropionic acid 2-phenylethyl was 0:100, so the reaction was terminated. The reaction solution was cooled to 5°C or less, and insoluble matter was removed by filtration. 20.4g of 10% hydrochloric acid was added to the filtrate, and the liquids were separated. Next, the organic layer was washed twice with 20.4g of 10% hydrochloric acid, 20.4g of water, and 20.4g of 10% aqueous potassium hydrogen carbonate solution, in that order. After further washing with 20.4g of water and 20.4g of 20% aqueous sodium chloride solution, the organic layer was dried over magnesium sulfate. The inorganic salts were filtered, and the filtrate was concentrated under reduced pressure with an evaporator at an external temperature of 30°C and 30mmHg. 4.0g (15.7mmol) of 2-phenylethyl 3-phenylpropionate was obtained as white crystals with a yield of 94.7% and an LC purity of 99.4%. 1 H-NMR(400MHz, CDCl3):δ2.61(2H,t,J=7.8Hz,Ph-CH2-C H 2-C(=O)-O-),2.88-2.94(4H,m,Ph-C H 2-CH2-C(=O)-O-and-C(=O)-O-CH2-C H 2-Ph),4.28(2H,t,J=7.1Hz,-C(=O)-OC H 2-CH2-Ph), 7.15-7.31(10H,m, Ph -CH2-and-CH2- Ph ); 13 C-NMR(100MHz,CDCl3):δ30.87(Ph- C H2-CH2-C(=O)-O-),35.05(-C(=O)-O-CH2- C H2-Ph), 35.84(Ph-CH2- C H2-C(=O)-O-), 64.89(-C(=O)-O- C H2-CH2-Ph),126.21,126.51,128.24,128.45,128.85,137.76,140.45( Ph -CH2-and-CH2- Ph ), 172.76(-CH2- C (=O)-O-CH2-).

[0057] Example 8 In a 100mL test tube, 20.4g of dichloromethane (10wt times) and 3.0g of 3-phenylpropionic acid (20.0mmol, 1.3mol times) were taken and cooled to below 5℃. 1.9g of 2-phenylethanol (15.4mmol) and 6.24g of DMT-MM (20.0mmol, 1.3mol times) were charged and stirred for 0.5 hours. After 0.5 hours, 0.24g of DMAP (2.0mmol, 13mol%) was added and aged for 1 hour at below 5℃, then heated to 30℃ and stirred at the same temperature for 23 hours. Analysis by LC showed that the ratio of the raw material 2-phenylethanol to the target 3-phenylpropionic acid 2-phenylethyl was 0:100, so the reaction was terminated. The reaction solution was cooled to below 5°C, and insoluble matter was removed by filtration. 20.4g of 10% hydrochloric acid was added to the filtrate, and the liquids were separated. The organic layer was then washed twice with 20.4g of 10% hydrochloric acid, 20.4g of water, and 20.4g of 10% aqueous potassium hydrogen carbonate solution, in that order. After further washing with 20.4g of water and 20.4g of 20% aqueous sodium chloride solution, the organic layer was dried over magnesium sulfate. The inorganic salts were filtered, and the filtrate was concentrated under reduced pressure in an evaporator at an external temperature of 30°C and 30mmHg. 3.7g (14.4mmol) of 2-phenylethyl 3-phenylpropionate was obtained as white crystals with a yield of 93.3% and an LC purity of 99.6%.

[0058] Example 9 13.6g of 95% ethanol (5% water, 6.8wt times) and 2.0g (13.3mmol) of 3-phenylpropionic acid were placed in a 100mL test tube and cooled to below 5℃. 0.18g (1.33mmol, 0.1mol times) of potassium carbonate and 4.2g (13.3mmol, 1.0mol times) of DMT-MM were added, and after aging for 30 minutes, 0.16g (1.33mmol, 10mol%) of DMAP was added. After aging for 1 hour at below 5℃, the temperature was raised to 30℃, and the mixture was stirred at the same temperature for 21 hours and analyzed by LC. The reaction solution was cooled to 5°C or less, and insoluble matter was removed by filtration. The filtrate was concentrated under reduced pressure in an evaporator at an external temperature of 40°C and 30mmHg, and 4.6g of a yellow solid was obtained. 13.9g of 50mM hydrochloric acid and 13.9g of toluene were added to the concentrated residue, and the liquids were separated. Next, the organic layer was washed with 13.9g of water, and washed twice with 13.9g of 10% aqueous potassium hydrogen carbonate solution. After further washing with 13.9g of water and 13.9g of 20% aqueous sodium chloride solution, the organic layer was dried over magnesium sulfate. The inorganic salts were filtered, and the filtrate was concentrated under reduced pressure in an evaporator at an external temperature of 60°C and 30mmHg, and 2.0g (11.4mmol) of ethyl 3-phenylpropionate was obtained as a colorless oily substance with a yield of 85.9% and an LC purity of 96.9%. 1 When calculated by H-NMR, the pure yield was 2.0 g, and the yield was 90.8%.

[0059] Example 10 20.4g (6.8wt times) of 2-propanol and 3.0g (20.0mmol) of 3-phenylpropionic acid were taken in a 100mL test tube and cooled to below 5℃. 0.28g (2.0mmol, 0.1mol times) of potassium carbonate and 7.49g (24.0mmol, 1.2mol times) of DMT-MM were charged and stirred for 1.5 hours. After 1.5 hours, 0.24g (2.0mmol, 10mol%) of DMAP was added. After aging for 1 hour at below 5℃, the temperature was raised to 30℃ and stirred at the same temperature for 19 hours. When analyzed by LC, the ratio of the raw material 3-phenylpropionic acid to the target 2-propyl 3-phenylpropionate was 1.3:98.7, so the reaction was terminated. The reaction solution was cooled to 5°C or less, and insoluble matter was filtered off. The filtrate was concentrated under reduced pressure in an evaporator at an external temperature of 40°C and 30mmHg, obtaining 5.3g of a yellow solid. 20.4g of 50mM hydrochloric acid and 20.4g of dichloromethane were added to the concentrated residue, and the liquids were separated. Next, the organic layer was washed with 20.4g of water, and washed twice with 20.4g of 10% aqueous potassium hydrogen carbonate solution. After further washing with 20.4g of water and 20.4g of 20% aqueous sodium chloride solution, the organic layer was dried over magnesium sulfate. The inorganic salts were filtered off, and the filtrate was concentrated under reduced pressure in an evaporator at an external temperature of 30°C and 30mmHg. 3.6g (18.8mmol) of 2-propyl 3-phenylpropionate was obtained as a colorless oily substance, with a yield of 94.0% and an LC purity of 96.3%. 1 When calculated by H-NMR, the pure yield was 3.6 g, and the calculated yield was 93.1%.

[0060] Comparative Example 1 (performed with reference to Non-Patent Document 3) 23.7g (7.9wt times) of 2-propanol and 3.0g (20.0mmol) of 3-phenylpropionic acid were placed in a 100mL test tube and stirred at an external temperature of 50℃. 6.55g (21.0mmol, 1.05mol times) of DMT-MM and 0.012g (0.1mmol, 0.5mol%) of DMAP were added. Stirred at the same temperature for 24 hours. Analysis by LC showed that the ratio of the raw material 3-phenylpropionic acid to the desired 2-propyl 3-phenylpropionate was 30.4:69.6. The reaction solution was filtered, and the filtrate was concentrated under reduced pressure in an evaporator at an external temperature of 50°C and 30mmHg. 23.7g of dichloromethane was added to the concentrated residue, and the mixture was washed twice with 23.7g of 10% hydrochloric acid. The organic layer was then washed in sequence with 23.7g of water, 23.7g of 10% aqueous potassium hydrogen carbonate solution, 23.7g of water, and 23.7g of 20% aqueous sodium chloride solution. The organic layer was dried over magnesium sulfate, and then the inorganic salts were filtered off, and the filtrate was concentrated under reduced pressure in an evaporator at an external temperature of 30°C and 30mmHg. 2.4g (18.8mmol) of 2-propyl 3-phenylpropionate was obtained as a colorless oily substance with a yield of 62.5% and an LC purity of 94.5%. 1 When calculated by H-NMR, the pure yield was 2.4 g, and the calculated yield was 62.1%. [Industrial Applicability]

[0061] The present invention is a method for producing esters with high purity and high yield, with high substrate generality. Since it can be applied to a wide variety of carboxylic acids and alcohols, a wide variety of esters can be freely produced. Ester bonds are frequently found in various products such as pharmaceuticals and agricultural chemicals, and the use of the present invention can be used suitably in a wide variety of fields.

Claims

1. A method for producing a carboxylic acid ester by condensing a carboxylic acid with an alcohol in the presence of 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride (DMT-MM), A method for producing a carboxylic acid ester, comprising: maintaining a reaction temperature at 15° C. or lower for at least 15 minutes after the start of the reaction; and adding 0.01 to 0.5 moles of 4-(dimethylamino)pyridine per mole of DMT-MM.

2. 2. The process according to claim 1, wherein the reaction temperature is 20° C. or higher 15 minutes after the start of the reaction.

3. 2. The process according to claim 1, wherein 4-(dimethylamino)pyridine is added at least 15 minutes after the start of the reaction.

4. The process according to claim 1, wherein the reaction is carried out in an aprotic solvent.

5. 2. The process according to claim 1, wherein the amount of DMT-MM used is 1 to 1.5 moles per mole of the carboxylic acid.

6. 2. The process according to claim 1, wherein the reaction temperature is 10° C. or lower for at least 15 minutes after the start of the reaction.

7. 2. The method according to claim 1, further comprising adding 0.01 to 0.5 mol of an organic or inorganic base other than 4-(dimethylamino)pyridine per 1 mol of DMT-MM.

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