Method for preparing carboxylic acid methyl ester by one-pot method

Abstract

The invention discloses a method for preparing carboxylic acid methyl ester by a one-pot method, which comprises the following step: reacting carboxylic acid with N-methyl-N-nitrosourea in an anhydrous organic solvent under the action of alkali to prepare the target product carboxylic acid methyl ester. According to the preparation method, N-methyl-N-nitrosourea which is high in reaction activity, low in price and easy to obtain is used as a diazomethane precursor to generate diazomethane in situ, the diazomethane reacts with carboxylic acid through a one-pot method to obtain corresponding carboxylic acid methyl ester, and direct use of a highly toxic and explosive diazomethane reagent is avoided. The preparation method disclosed by the invention has the characteristics of simple and mild reaction conditions, convenience in post-treatment, green steps, low pollution, high economic benefit and the like.

Description

Technical Field

[0001] The present invention belongs to the technical field of organic compound synthesis, and particularly relates to a method for preparing methyl carboxylate by a one-pot method. Background Art

[0002] The reaction of carboxylic acid with diazomethane is an important method for preparing methyl carboxylate. The reaction is efficient and rapid, and the by-product is only nitrogen, which is widely used in the derivatization and modification of biological macromolecules such as amino acids, proteins, and nucleic acids. However, diazomethane gas is highly toxic, explosive, and has poor stability, making it difficult to store and transport. Using a diazomethane precursor to in-situ prepare diazomethane by a "one-pot method" to participate in the reaction can reduce safety hazards. At present, the preparation of diazomethane by a "one-pot method" using a diazomethane precursor has been reported, but all existing "one-pot method" preparation methods of diazomethane require the addition of water to initiate the decomposition of the diazomethane precursor, so they are not applicable to water-sensitive reaction substrates or some complex reactions. Summary of the Invention

[0003] The purpose of this part is to outline some aspects of the embodiments of the present invention and briefly introduce some preferred embodiments. Simplifications or omissions may be made in this part, as well as in the abstract and title of the present application, to avoid obscuring the purpose of this part, the abstract, and the title, but such simplifications or omissions shall not be used to limit the scope of the present invention.

[0004] In view of the above and / or problems existing in the prior art, the present invention is proposed.

[0005] One of the purposes of the present invention is to provide a method for preparing methyl carboxylate by a one-pot method, which realizes the in-situ generation and participation of diazomethane in a pure organic phase condition, and effectively expands the scope of carboxylic acid substrates for the method of realizing carboxylic acid methylation. It has the characteristics of simple reaction conditions, convenient post-treatment, green steps, low pollution, and high economic benefits.

[0006] To solve the above technical problems, the present invention provides the following technical solution: A method for preparing methyl carboxylate by a one-pot method, comprising reacting a carboxylic acid represented by formula I with N-methyl-N-nitrosourea represented by formula II in an anhydrous organic solvent under the action of a base to prepare a methyl carboxylate represented by formula III;

[0007] R-COOH (Formula I);

[0008]

[0009] R-COOMe (Formula III);

[0010] Wherein, R is an alkyl, cycloalkyl, aryl, or heteroaryl group, and the alkyl, cycloalkyl, aryl, and heteroaryl are optionally substituted by a halogen or an unsaturated group.

[0011] As a preferred embodiment of the method for preparing methyl carboxylate by the one-pot method of the present invention, wherein: the molar ratio of the carboxylic acid to N-methyl-N-nitrosourea is 1:1 to 3; preferably 1:2 or 1:3.

[0012] As a preferred embodiment of the method for preparing methyl carboxylate by the one-pot method of the present invention, wherein: the base is one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate, sodium bicarbonate, cesium carbonate, potassium tert-butoxide, sodium tert-butoxide; the preferred base is sodium carbonate or potassium hydroxide.

[0013] As a preferred embodiment of the method for preparing methyl carboxylate by the one-pot method of the present invention, wherein: the molar ratio of the base to the carboxylic acid is 1 to 3:1; preferably the molar ratio of the base to the carboxylic acid is 2:1.

[0014] As a preferred embodiment of the method for preparing methyl carboxylate by the one-pot method of the present invention, wherein: the solvent is one of acetonitrile, tetrahydrofuran, dichloromethane, ethylene glycol dimethyl ether, 1,4-dioxane, ethanol, N,N-dimethylformamide, N,N-dimethylacetamide, N-methylpyrrolidone; the preferred solvent is acetonitrile.

[0015] As a preferred embodiment of the method for preparing methyl carboxylate by the one-pot method of the present invention, wherein: the reaction temperature is 0 to 40 °C; preferably the reaction temperature is room temperature.

[0016] The reaction equation under the optimal conditions of the present invention is:

[0017]

[0018] Compared with the prior art, the present invention has the following beneficial effects:

[0019] The present invention provides a method for preparing dry diazomethane by a "one-pot method" and using it for carboxyl methylation. Using a highly active diazomethane precursor, water addition for initiation is not required, and diazomethane can be generated at room temperature; N-methyl-N-nitrosourea, as a highly active diazomethane precursor, has the advantages of easy preparation, low cost and easy availability. The "one-pot method" for realizing carboxyl methylation also avoids the use of the highly toxic and explosive reagent diazomethane. The method of the present invention has the characteristics of simple reaction conditions, convenient post-treatment, green steps, low pollution and high economic benefits. BRIEF DESCRIPTION OF THE DRAWINGS

[0020] In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the following will briefly introduce the drawings required for the description of the embodiments. Obviously, the following drawings are only some embodiments of the present invention. For those of ordinary skill in the art, without creative efforts, other drawings can also be obtained based on these drawings. Among them:

[0021] Figure 1 1H NMR spectrum of methyl 4 - methoxybenzoate, the target product of Example 1 of the present invention;

[0022] Figure 2 13C NMR spectrum of methyl 4 - methoxybenzoate, the target product of Example 1 of the present invention;

[0023] Figure 3 1H NMR spectrum of methyl benzoate, the target product of Example 2 of the present invention;

[0024] Figure 4 13C NMR spectrum of methyl benzoate, the target product of Example 2 of the present invention;

[0025] Figure 5 1H NMR spectrum of methyl 4 - aminobenzoate, the target product of Example 3 of the present invention;

[0026] Figure 6 13C NMR spectrum of methyl 4 - aminobenzoate, the target product of Example 3 of the present invention;

[0027] Figure 7 1H NMR spectrum of methyl cinnamate, the target product of Example 4 of the present invention;

[0028] Figure 8 13C NMR spectrum of methyl cinnamate, the target product of Example 4 of the present invention;

[0029] Figure 9 1H NMR spectrum of methyl 3 - phenylpropionate, the target product of Example 5 of the present invention;

[0030] Figure 10 13C NMR spectrum of methyl 3 - phenylpropionate, the target product of Example 5 of the present invention;

[0031] Figure 11 1H NMR spectrum of methyl BOC - L - tryptophanate, the target product of Example 6 of the present invention;

[0032] Figure 12 13C NMR spectrum of methyl BOC - L - tryptophanate, the target product of Example 6 of the present invention. Detailed Description of the Invention

[0033] To make the above - mentioned objects, features and advantages of the present invention more obvious and understandable, the following detailed description of the specific embodiments of the present invention will be given in conjunction with the embodiments of the specification.

[0034] In the following description, many specific details are set forth to facilitate a full understanding of the present invention. However, the present invention may be practiced in other ways different from those described herein. Those skilled in the art can make similar extensions without departing from the connotation of the present invention. Therefore, the present invention is not limited by the specific embodiments disclosed below.

[0035] Secondly, the so-called "one embodiment" or "embodiment" herein refers to a specific feature, structure, or characteristic that may be included in at least one implementation manner of the present invention. The phrase "in one embodiment" appearing in different places in this specification does not necessarily refer to the same embodiment, nor is it an individual or alternative embodiment that is mutually exclusive with other embodiments.

[0036] Unless otherwise specified, the raw materials used in the examples are all commercially purchased.

[0037] Example 1

[0038] (1) 4-Methoxybenzoic acid (0.5 mmol, 1 equiv.), N-methyl-N-nitrosourea (1.0 mmol, 2 equiv.), sodium carbonate (1.0 mmol, 2 equiv.), and 2.5 mL of acetonitrile were successively added to a 10 mL reaction tube, and the reaction mixture was stirred overnight at room temperature.

[0039] (2) After the reaction was completed, 10 mL of saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with sodium carbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The target product, methyl 4-methoxybenzoate, was obtained without further purification. The structural formula of this compound is:

[0040]

[0041] The methyl 4-methoxybenzoate obtained above was characterized as follows Figure 1 and 2 The results were as follows: white solid; 1 1H NMR (400 MHz, CDCl3) δ 8.02–7.94 (m, 2H), 6.95–6.86 (m, 2H), 3.87 (s, 3H), 3.84 (s, 3H) ppm. 13 13C NMR (101 MHz, CDCl3) δ 166.8, 163.3, 131.5, 122.5, 113.5, 55.4, 51.8 ppm. HRMS (ESI) m / z calcd. for C9H 11 O3 + 167.0708, found 167.0708 [M+H] + .

[0042] Based on the characterization data, it can be known that the prepared reaction product is methyl 4-methoxybenzoate (purity > 98%); the product yield was calculated, and the result was 96%.

[0043] Example 2

[0044] (1) To a 10 mL reaction tube, add benzoic acid (0.5 mmol, 1 equiv.), N-methyl-N-nitrosourea (1.0 mmol, 2 equiv.), sodium carbonate (1.0 mmol, 2 equiv.) and 2.5 mL of acetonitrile in sequence, and stir the reaction mixture at room temperature overnight.

[0045] (2) After the reaction is completed, add 10 mL of saturated ammonium chloride solution to quench the reaction, extract with ethyl acetate, wash the organic phase with sodium carbonate solution and saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate the solvent by rotary evaporation to obtain the target product methyl benzoate without further purification. The structural formula of this compound is:

[0046]

[0047] Characterize the above methyl benzoate, as Figure 3 and 4 shown, the results are: white solid; 1 1H NMR (400 MHz, CDCl3) δ 8.08–8.00 (m, 2H), 7.60–7.51 (m, 1H), 7.48–7.39 (m, 2H), 3.92 (s, 3H) ppm. 13 13C NMR (101 MHz, CDCl3) δ 167.1, 132.9, 130.1, 129.5, 128.3, 52.1 ppm. HRMS (ESI) m / z calcd. for C8H9O2 + 137.0603, found 137.0605 [M+H] + .

[0048] According to the characterization data, the prepared reaction product is methyl benzoate (purity > 98%); calculate the product yield, and the result is 86%.

[0049] Example 3

[0050] (1) To a 10 mL reaction tube, add 4-aminobenzoic acid (0.5 mmol, 1 equiv.), N-methyl-N-nitrosourea (1.0 mmol, 2 equiv.), sodium carbonate (1.0 mmol, 2 equiv.) and 2.5 mL of acetonitrile in sequence, and stir the reaction mixture at room temperature overnight.

[0051] (2) After the reaction is completed, add 10 mL of saturated ammonium chloride solution to quench the reaction, extract with ethyl acetate, wash the organic phase with sodium carbonate solution and saturated sodium chloride solution, dry over anhydrous sodium sulfate, and concentrate the solvent by rotary evaporation to obtain the target product methyl 4-aminobenzoate. The structural formula of this compound is:

[0052]

[0053] The methyl 4-aminobenzoate above was characterized as follows Figure 5 and 6 shown below. The results were as follows: white solid; 1 1H NMR (400 MHz, CDCl3) δ 7.99–7.72 (m, 2H), 6.74–6.52 (m, 2H), 4.05 (brs, 2H), 3.85 (s, 3H) ppm. 13 13C NMR (101 MHz, CDCl3) δ 167.1, 150.8, 131.6, 119.7, 113.8, 51.6 ppm. HRMS (ESI) m / z calcd. for C8H 10 NO2 + 152.0712, found 152.0710 [M+H] + .

[0054] According to the characterization data, the reaction product obtained was methyl 4-aminobenzoate (purity > 98%); the product yield was calculated, and the result was 75%.

[0055] Example 4

[0056] (1) Cinnamic acid (0.5 mmol, 1 equiv.), N-methyl-N-nitrosourea (1.0 mmol, 2 equiv.), sodium carbonate (1.0 mmol, 2 equiv.) and 2.5 mL of acetonitrile were successively added to a 10 mL reaction tube, and the reaction mixture was stirred at room temperature overnight.

[0057] (2) After the reaction was completed, 10 mL of saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with sodium carbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The target product, methyl cinnamate, was obtained without further purification. The structural formula of this compound is:

[0058]

[0059] The methyl cinnamate above was characterized as follows Figure 1 and 2 shown below. The results were as follows: white solid; 1 H 11H NMR (400 MHz, CDCl3) δ 7.70 (d, J = 16.0 Hz, 1H), 7.55–7.49 (m, 2H), 7.41–7.36 (m, 3H), 6.44 (d, J = 16.0 Hz, 1H), 3.81 (s, 3H) ppm. 13 13C NMR (101 MHz, CDCl3) δ 167.4, 144.8, 134.3, 130.2, 128.8, 128.0, 117.7, 51.6 ppm. HRMS (ESI) m / z calcd. for C 10 H 11 O2 + 163.0759, found 163.0760 [M+H] + .

[0060] According to the characterization data, the prepared reaction product is methyl cinnamate (purity > 98%); the product yield was calculated, and the result was 76%.

[0061] Example 5

[0062] (1) 3-Phenylpropionic acid (0.5 mmol, 1 equiv.), N-methyl-N-nitrosourea (1.0 mmol, 2 equiv.), sodium carbonate (1.0 mmol, 2 equiv.) and 2.5 mL of acetonitrile were successively added to a 10 mL reaction tube, and the reaction mixture was stirred at room temperature overnight.

[0063] (2) After the reaction was completed, 10 mL of saturated ammonium chloride solution was added to quench the reaction, and the mixture was extracted with ethyl acetate. The organic phase was washed with sodium carbonate solution and saturated sodium chloride solution, dried over anhydrous sodium sulfate, and the solvent was removed by rotary evaporation. The target product, methyl 3-phenylpropionate, was obtained without further purification. The structural formula of this compound is:

[0064]

[0065] The above methyl 3-phenylpropionate was characterized, and the results were: white solid; 1 1H NMR (400 MHz, CDCl3) δ 7.33–7.26 (m, 2H), 7.23 - 7.19 (m, 3H), 3.68 (s, 3H), 2.96 (t, J = 7.8 Hz, 2H), 2.68–2.61 (m, 2H) ppm. 13 13C NMR (101 MHz, CDCl3) δ 173.3, 140.5, 128.5, 128.2, 126.2, 51.6, 35.7, 30.9 ppm. HRMS (ESI) m / z calcd. for C 10 H13 O2 + 165.0916, found 165.0920 [M+H] + .

[0066] According to the characterization data, the prepared reaction product is methyl 3-phenylpropionate (purity > 98%); the product yield was calculated, and the result was 80%.

[0067] Example 6

[0068] (1) Sequentially add BOC-L-tryptophan methyl ester (0.5 mmol, 1 equiv.), N-methyl-N-nitrosourea (1.0 mmol, 2 equiv.), sodium carbonate (1.0 mmol, 2 equiv.) and 2.5 mL of acetonitrile to a 10 mL reaction tube, and stir the reaction mixture at room temperature overnight.

[0069] (2) After the reaction is completed, add 10 mL of saturated ammonium chloride solution to quench the reaction, extract with ethyl acetate, wash the organic phase with sodium carbonate solution and saturated sodium chloride solution, dry over anhydrous sodium sulfate, and then concentrate the solvent by rotary evaporation to obtain the target product BOC-L-tryptophan methyl ester without further purification. The structural formula of this compound is:

[0070]

[0071] The above BOC-L-tryptophan methyl ester was characterized, and the results were: white solid; 1 H NMR (400 MHz, CDCl3) δ 8.22 (s, 1H), 7.55 (d, J = 7.9 Hz, 1H), 7.34 (d, J = 8.1 Hz, 1H), 7.22–7.16 (m, 1H), 7.14–7.08 (m, 1H), 6.98 (d, J = 2.4 Hz, 1H), 5.09 (d, J = 8.2 Hz, 1H), 4.68 - 4.63 (m, 1H), 3.68 (s, 3H), 3.30 - 3.28 (m, 2H), 1.43 (s, 9H) ppm. 13 C NMR (101 MHz, CDCl3) δ 172.8, 155.2, 136.1, 127.6, 122.7, 122.1, 119.6, 118.7, 111.2, 110.1, 79.8, 54.2, 52.2, 28.3, 28.0 ppm. HRMS (ESI) m / z calcd. for C 17 H 23 N2O4 + 319.1658, found 319.1658 [M+H] + .

[0072] According to the characterization data, the prepared reaction product is BOC-L-tryptophan methyl ester (purity > 98%); the product yield is calculated, and the result is 81%.

[0073] Example 7

[0074] Example 7 is basically the same as Example 1, except that the base in step (1) is different, as shown in Table 1 below.

[0075] Table 1

[0076] base Yield (%) none 0 potassium hydroxide 96 sodium bicarbonate 90 sodium carbonate 96 potassium carbonate 88 sodium bicarbonate 33 triethylamine 76

[0077] As can be seen from Table 1, without the additive base, the reaction cannot proceed. Under the same reaction conditions, for different bases such as potassium hydroxide, sodium hydroxide, potassium carbonate, sodium bicarbonate, and triethylamine, the synthesis can be successfully carried out. The effects of sodium carbonate and potassium hydroxide are the best, and the highest yield is 96%.

[0078] Example 8

[0079] Example 8 is basically the same as Example 1, except that the equivalent of the base in step (1) is different, as shown in Table 2 below.

[0080] Table 2

[0081] equivalent yield 1 93％ 2 96％ 3 90％ 4 74％

[0082] As can be seen from Table 2, under the same reaction conditions, the synthesis can be successfully carried out for different equivalents of the base. The effect of 2 equivalents is the best, and the highest yield is 96%. Increasing the equivalent of the base will cause the ester to hydrolyze back to the acid, affecting the reaction yield.

[0083] Example 9

[0084] Example 9 is basically the same as Example 1, except that the diazomethane precursor in step (1) is different, as shown in Table 3 below.

[0085] Table 3

[0086] diazomethane precursor yield MNNG 43％ Diazald trace STZ 23％ TMZ trace

[0087] As can be seen from Table 3, under the same reaction conditions, for different diazomethane precursors such as Diazald (N-methyl-N-nitrosotoluenesulfonamide) and TMZ (temozolomide), the reaction hardly proceeds; while for MNNG (N-methyl-N'-nitro-N-nitrosoguanidine) and STZ (streptozotocin) as diazomethane precursors, the target product can be successfully synthesized, but the reaction yield is low.

[0088] Example 10

[0089] Example 10 is basically the same as Example 1, except that the equivalent amount of NMU in step (1) is different, as shown in Table 4 below.

[0090] Table 4

[0091]

[0092]

[0093] As can be seen from Table 4, under the same reaction conditions, different equivalent amounts of urea, such as 1 equivalent, 2 equivalents, and 3 equivalents, can all be successfully synthesized, with the best results obtained with 2 or 3 equivalents and a maximum yield of 98%.

[0094] Example 11

[0095] Example 11 is basically the same as Example 1, except that the solvent in step (1) is different, as shown in Table 5 below.

[0096] Table 5

[0097] solvent yield dichloromethane 69％ ethylene glycol dimethyl ether 66％ ethanol 50％ tetrahydrofuran 65％

[0098] As can be seen from Table 5, under the same reaction conditions, different solvents, such as dichloromethane, ethylene glycol dimethyl ether, ethanol, and tetrahydrofuran, can all be successfully synthesized, but the yields are relatively low.

[0099] Example 12

[0100] Example 12 is basically the same as Example 1, except that the carboxylic acid substrate in step (1) is different, as shown in Table 6 below:

[0101] Table 6

[0102]

[0103]

[0104] The present invention provides a method for preparing a dry diazomethane solution for the synthesis of methyl carboxylate by a "one-pot" method, belonging to the technical field of organic compound synthesis. By adding a diazomethane precursor N-methyl-N-nitrosourea (NMU), a base, a carboxylic acid, and an organic solvent to a reaction vessel in a certain ratio by the "one-pot" method, the corresponding methyl carboxylate can be obtained in moderate to good yields.

[0105] The preparation method of the present invention uses highly reactive and cheaply available N-methyl-N-nitrosourea (NMU) as a diazomethane precursor to in-situ generate diazomethane, and reacts with carboxylic acids through a "one-pot method" to obtain the corresponding methyl carboxylates, avoiding the direct use of highly toxic and explosive diazomethane reagents. NMU has high reactivity and does not require the addition of water to initiate the decomposition of the diazomethane precursor, so it can be applied to water-sensitive reaction substrates. The preparation method of the present invention has simple and mild reaction conditions, and has the characteristics of convenient post-treatment, green steps, low pollution, and high economic benefits.

[0106] It should be noted that the above embodiments are only used to illustrate the technical solutions of the present invention and not to limit them. Although the present invention has been described in detail with reference to the preferred embodiments, those of ordinary skill in the art should understand that the technical solutions of the present invention can be modified or equivalently replaced without departing from the spirit and scope of the technical solutions of the present invention, and they should all be covered within the scope of the claims of the present invention.

Claims

1. A one-pot method for preparing methyl carboxylate, characterized in that: include, The carboxylic acid represented by formula I and the N-methyl-N-nitrosourea represented by formula II are reacted in an anhydrous organic solvent under the action of a base to prepare a carboxylic acid methyl ester represented by formula III; R-COOH (Formula I); R-COOMe (Formula III); Wherein, R is an alkyl group, a cycloalkyl group, an aryl group, or a heteroaryl group, and the alkyl group, the cycloalkyl group, the aryl group, the heteroaryl group is optionally substituted by a halogen or an unsaturated group.

2. The one-pot method for preparing methyl carboxylate according to claim 1, wherein: The molar ratio of the carboxylic acid to N-methyl-N-nitrosourea is 1:1-3.

3. The one-pot method for preparing methyl carboxylate according to claim 1, characterized in that: The alkali is one of sodium hydroxide, potassium hydroxide, sodium carbonate, potassium carbonate, sodium phosphate, sodium bicarbonate, cesium carbonate, potassium tert-butoxide, and sodium tert-butoxide.

4. The one-pot method for preparing methyl carboxylate according to claim 3, characterized in that: The base is sodium carbonate or potassium hydroxide.

5. The one-pot method for preparing methyl carboxylate according to claim 3 or 4, characterized in that: The molar ratio of the base to the carboxylic acid is 1 to 3:

1.

6. The one-pot method for preparing methyl carboxylate according to claim 5, characterized in that: The molar ratio of the base to the carboxylic acid is 2:

1.

7. The one-pot method for preparing methyl carboxylate according to any one of claims 2, 3, 4 and 6, characterized in that: The solvent is one of acetonitrile, tetrahydrofuran, dichloromethane, ethylene glycol dimethyl ether, 1,4-dioxane, ethanol, N,N-dimethylformamide, N,N-dimethylacetamide and N-methylpyrrolidone.

8. The one-pot method for preparing methyl carboxylate according to claim 7, characterized in that: The solvent is acetonitrile.

9. The one-pot method for preparing methyl carboxylate according to any one of claims 2, 3, 4, 6, and 8, characterized in that: The reaction temperature is 0-40°C.

10. The one-pot method for preparing methyl carboxylate according to claim 9, characterized in that: The method also includes the step of purifying the reaction product.

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