A method for synthesizing non-cyclic tertiary amide

Abstract

The present invention relates to the field of compound preparation, and in particular to a method for synthesizing a non-cyclic tertiary amide, the innovation of which lies in the use of a ligand with a small steric hindrance near the coordination active center site and containing a coordinating atom at the β-position, and the oxamide ligand used is N,N'-di(2-morpholineethyl)oxamide, which can promote the C-N coupling reaction of N-substituted benzamide derivatives and differently substituted (hetero)aryl halide compounds. The ligand provided by the present invention is novel, the preparation method is simple, the reaction conditions are mild, the environment is friendly, and the applicable substrate is relatively wide.

Description

Technical Field

[0001] The present invention relates to the field of compound synthesis, and in particular to a method for synthesizing a non-cyclic tertiary amide. Background Art

[0002] The synthesis of amide bonds is one of the most frequently used reaction types in medicinal chemistry, accounting for about 50%, and about two-thirds of drugs and drug candidates contain amide structures, which is enough to reflect the importance of amide bonds in medicinal chemistry. As a common functional group, the tertiary amide bond has shown unique advantages in the design of special active compounds due to its characteristic of only being a hydrogen bond acceptor. Therefore, it is widely used in many commercial pesticides and pharmaceutical molecules, such as apixaban, ezetimibe, bromofenac insecticides and acetochlor herbicides.

[0003] From the perspective of retrosynthesis, there are two classical synthesis methods for tertiary amide bonds: the first method is to obtain tertiary amides by condensation reaction of corresponding carboxylic acids or carboxylic acid derivatives with secondary amines; the second method is to obtain tertiary amides by N-alkylation reaction of corresponding secondary amides with halogenated hydrocarbons. In the first method, carboxylic acid derivatives (such as acyl chlorides, anhydrides and esters, etc.) are required to react with corresponding secondary amines for aminolysis to prepare tertiary amides. Although this method can directly construct tertiary amides, it is necessary to prepare carboxylic acids into corresponding derivatives in advance, which not only increases the reaction steps but also increases the reaction cost. While directly using carboxylic acids and corresponding amines to synthesize tertiary amides under the action of condensation agents reduces the reaction steps, the use of equivalent or excess condensation agents not only increases the reaction cost, but also increases the difficulty of post-processing. Compared with the first method, directly using the corresponding secondary amides to carry out N-alkylation reaction to synthesize tertiary amides (the second method) can avoid the above shortcomings, especially the metal-catalyzed N-alkylation reaction, which can greatly reduce the reaction cost, which has stimulated the research interest of many research groups. However, due to the p-π conjugation between the nitrogen atom of the amide and the carbonyl group, the nucleophilicity of the nitrogen atom of the amide is greatly reduced. At the same time, due to the influence of the substituent on the nitrogen atom, the steric hindrance of the nitrogen atom is increased. These two unfavorable factors together increase the difficulty of the N-alkylation reaction of secondary amides, especially non-cyclic secondary amides. It is found that metals such as palladium, nickel, iron or copper can catalyze the cross-coupling reaction to form CN bonds, but metals such as palladium and nickel are expensive, which increases the reaction cost and is difficult to achieve large-scale production. Compared with metals such as palladium and nickel, copper is cheap and easy to obtain, and is a more ideal catalyst. Therefore, using copper as a catalyst and under the promotion of the corresponding ligand, the direct synthesis of tertiary amides from secondary amides has become one of the important development directions.

[0004] At present, there have been reports on the use of oxalamide ligands to promote the copper-catalyzed Ullmann reaction to synthesize tertiary amides. For example, N,N'-bis(2-thienylmethyl)oxalamide and N,N'-bis(2-pyridylmethyl)oxalamide can promote the synthesis of cyclic tertiary amides. However, this ligand is not suitable for promoting the synthesis of non-cyclic tertiary amides. Therefore, it is necessary to develop new ligands to promote the synthesis of non-cyclic tertiary amides. Summary of the invention

[0005] The present invention aims at many problems existing in the prior art and provides a method for synthesizing a non-cyclic tertiary amide. The innovation of the method lies in the use of a ligand with a small steric hindrance near the coordination active center and containing a coordinating atom at the β-position. The oxamide ligand used is N,N'-di(2-morpholinoethyl)oxamide, which can promote the coupling reaction of CuTc-catalyzed non-cyclic secondary amide and aryl halide compound in an ultra-dry dimethyl sulfoxide solution at 60-140°C, and the target product is separated by column chromatography. The ligand used in the present invention is novel and the preparation method is simple; the reaction conditions are mild, the environment is friendly, and the applicable substrate is relatively wide.

[0006] The specific technical solutions of the present invention are as follows:

[0007] The inventors first provided the use of N,N'-bis(2-morpholinoethyl)oxalamide in the synthesis of non-cyclic tertiary amides. The structural formula of the N,N'-bis(2-morpholinoethyl)oxalamide is as follows:

[0008]

[0009] The above-mentioned N,N'-di(2-morpholinoethyl)oxamide has less steric hindrance at the site near the coordination active center and contains a coordinating atom at the β-position, and has the best promoting effect on the synthesis of non-cyclic tertiary amides.

[0010] The non-cyclic tertiary amide structure is as follows:

[0011]

[0012] Wherein R1 is an aromatic derivative, R2 is an alkyl group or an aromatic derivative, and R3 is an aromatic derivative;

[0013] More specifically, the acyclic tertiary amide may be:

[0014]

[0015] Furthermore, the present application also provides a method for synthesizing a non-cyclic tertiary amide, the specific steps of which are as follows:

[0016] N,N'-di(2-morpholinoethyl)oxalamide promotes the coupling reaction of non-cyclic secondary amide and aryl halide compound catalyzed by CuTc in ultra-dry dimethyl sulfoxide solution at 60-140°C, and the target product is separated by column chromatography;

[0017] A more specific synthesis method is as follows:

[0018] In a glove box, the non-cyclic secondary amide and NaH are placed in a pressure-resistant reaction bottle, 1 mL of dimethyl sulfoxide is added, and the mixture is stirred until bubbles are scarce, and then N, N'-di(2-morpholinoethyl)oxalamide and CuTc are added and stirred until bubbles are scarce, and finally, the aryl halide compound is added, the mixture is sealed, removed from the glove box, and placed in an oil bath at 60-140°C for reaction for 12-24 hours. After the reaction is completed, the mixture is extracted with saturated brine and ethyl acetate, the organic phase is collected, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain pure non-cyclic tertiary amide.

[0019] The molar ratio of NaH to the non-cyclic secondary amide is in the range of 1-2.5:1;

[0020] The ratio of the non-cyclic secondary amide to dimethyl sulfoxide is 1-3 ml of dimethyl sulfoxide for 1 mmol of the non-cyclic secondary amide;

[0021] The ratio of N,N'-di(2-morpholinoethyl)oxalamide as a promoter to the non-cyclic secondary amide is 0.05-0.3:1;

[0022] The molar ratio of N,N'-di(2-morpholinoethyl)oxalamide to CuTc is in the range of 1-2:1;

[0023] The molar ratio of the aryl halide compound to the non-cyclic secondary amide is in the range of 1-1.5:1;

[0024] The non-cyclic secondary amide structure used is as follows:

[0025]

[0026] Wherein R1 is an aromatic derivative, and R2 is an alkyl group or an aromatic derivative;

[0027] The structural formula of the aryl halide compound used is as follows:

[0028]

[0029] Wherein X=I, Br or Cl, R1 is hydrogen or alkyl or halogen or trifluoromethyl or methoxy or methylthio;

[0030] The reaction conditions in the above reaction are further preferably a reaction temperature of 100°C and a reaction time of 24h, and the corresponding aryl halide compound is a bromide with slightly lower activity; or a reaction temperature of 60°C and a reaction time of 18h, and the corresponding aryl halide compound is an iodide with higher activity; or a reaction temperature of 140°C and a reaction time of 12h, and the corresponding aryl halide compound is a chloride with the lowest activity.

[0031] In addition, the steps of collecting the organic phase, drying with anhydrous sodium sulfate, and column chromatography separation are all completed using existing technologies, and the inventors will not elaborate on them.

[0032] Compared with the existing non-cyclic tertiary amide synthesis method, the present application has the following beneficial effects:

[0033] The present application solves the problems of high cost and difficulty in post-processing when synthesizing tertiary amides by condensation reaction of corresponding carboxylic acids or carboxylic acid derivatives with secondary amines; for copper-catalyzed N-arylation reaction of secondary amides, the present application solves the problem that current methods mainly focus on the N-arylation reaction of lactams with less steric hindrance or non-cyclic secondary amides with slightly stronger nucleophilicity; it can not only be used to promote the N-arylation reaction of more active and more expensive aromatic iodine compounds with non-cyclic secondary amides, but also can be used to promote the N-arylation reaction of less active and less expensive aromatic bromide or chlorine compounds with non-cyclic secondary amides, and has a wider scope of application. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 and 2 is the NMR spectrum of compound (3);

[0035] Figure 3 and 4 is the NMR spectrum of compound (5);

[0036] Figure 5 and 6 This is the NMR spectrum of compound (8). DETAILED DESCRIPTION

[0037] The present invention is further illustrated below in conjunction with embodiments. It is necessary to point out here that the following embodiments cannot be understood as limiting the scope of protection of the present invention. If a person skilled in the art makes some non-essential improvements and adjustments to the present invention based on the above-mentioned contents of the present invention, they still fall within the scope of protection of the present invention.

[0038] Example 1

[0039] Determination of relevant conditions for the synthesis of non-cyclic tertiary amides:

[0040] The inventors investigated the types of ligands, catalysts, bases, solvents, reaction temperatures and reaction times. First, N-methylbenzamide and bromobenzene were used as template substrates, cuprous iodide (CuI) was used as a metal catalyst, potassium tert-butoxide (KOtBu) was used as a base, and dimethyl sulfoxide (DMSO) was used as a solvent. The reaction was carried out at a temperature of 145° C. for 12 hours to screen the ligands. The specific results are shown in the following table:

[0041]

[0042]

[0043] In this example, the inventors conducted a reactivity study on the ligands and found that the ligands with less steric hindrance near the active center and containing coordinating atoms at the β-position had the best promoting effect on the synthesis of non-cyclic tertiary amides, and the ligand L18 had the best promoting effect.

[0044] The inventors used L18 as a ligand and investigated the type of copper catalyst, the type of base, the type of solvent, the reaction temperature and the reaction time. The specific situation is shown in the following table:

[0045]

[0046] After trying different ligands, copper catalysts, bases and reaction solvents, and screening the reaction temperature and reaction time, the inventors finally found that the catalyst used was CuTc, the ligand used was N,N'-di(2-morpholinoethyl)oxamide, the base used was NaH, and the ratio of the ingredients was 20mol%:20mol%:150mol%; the solvent used was ultra-dry dimethyl sulfoxide, the reaction temperature was 100°C, and the reaction time was 24h, which corresponded to the conditions in item 11, and the yield was the highest, which was 85%.

[0047] Based on the above reaction conditions, the inventors provide a synthesis step of non-cyclic tertiary amide: in a glove box, non-cyclic secondary amide and NaH are placed in a pressure-resistant reaction bottle, 1 mL of dimethyl sulfoxide is added, and the mixture is stirred until bubbles are scarce, and then N, N'-di(2-morpholinoethyl)oxalamide and CuTc are added and stirred until bubbles are scarce, and finally, an aryl halide compound is added, the mixture is sealed, removed from the glove box, and placed in an oil bath pot at 60-140°C for reaction for 12-24 hours. After the reaction is completed, the mixture is extracted with saturated brine and ethyl acetate, the organic phase is collected, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain pure non-cyclic tertiary amide.

[0048] The molar ratio of NaH to the non-cyclic secondary amide is in the range of 1-2.5:1;

[0049] The ratio of the non-cyclic secondary amide to dimethyl sulfoxide is 1-3 ml of dimethyl sulfoxide for 1 mmol of the non-cyclic secondary amide;

[0050] The ratio of N,N'-di(2-morpholinoethyl)oxalamide as a promoter to the non-cyclic secondary amide is 0.05-0.3:1;

[0051] The molar ratio of N,N'-di(2-morpholinoethyl)oxalamide to CuTc is in the range of 1-2:1;

[0052] The molar ratio of the aryl halide compound to the non-cyclic secondary amide is in the range of 1-1.5:1.

[0053] Example 2 Synthesis of N-methyl-N-(4-(trifluoromethyl)phenyl)benzamide

[0054]

[0055] In a glove box, N-methylbenzamide (1.2mmol) and NaH (1.5mmol) were mixed, 1mL of ultra-dry dimethyl sulfoxide was added, and the mixture was stirred until bubbles were rare, followed by the addition of N,N'-di(2-morpholinoethyl)oxalamide (0.2mmol) and CuTc (0.2mmol), and the mixture was stirred until bubbles were rare, and finally 4-trifluoromethyliodobenzene (1mmol) was added, the mixture was sealed, removed from the glove box, and placed in an oil bath at 60°C for 18h. After the reaction was completed, the mixture was extracted with ethyl acetate and saturated brine, the organic phase was collected, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain a yellow solid with a yield of 87%. The NMR spectrum of compound (3) is shown in FIG. Figure 1 and 2 As shown:

[0056] HRMS-ESI(m / z)calcd for C 15 H 13 F3NO(M+H):280.0949,found:280.0951

[0057] mp39–40℃, 1 H NMR (400MHz, CDCl3) δ7.47 (d, J = 8.2Hz, 2H), 7.30 (t, J = 7.4Hz, 3H), 7.21–7.15 (m, J = 21.9, 7.9Hz, 4H), 3.51 (s, 3H). 13 C NMR (101MHz, CDCl3) δ170.60,148.05,135.33,130.12,128.68,128.03,126.79,126.23,38.16.

[0058] Comparative Example 1

[0059] In 2015, Deepak Chopra et al. first synthesized N-(4-(trifluoromethyl)phenyl)benzoyl with benzoyl chloride and 4-trifluoromethylaniline, and then added iodide and NaH to synthesize N-methyl-N-(4-(trifluoromethyl)phenyl)benzamide. The yield of the product obtained by this method is 86%, but the operation of this method is complicated, and the raw materials are easy to deteriorate - benzoyl chloride reacts with water, iodide is easily decomposed by light, and is easily oxidized in the air.

[0060] Example 3 Synthesis of N-methyl-N-phenylbenzamide

[0061]

[0062] In a glove box, N-methylbenzamide (1.2mmol) and NaH (1.5mmol) were mixed, 1mL of ultra-dry dimethyl sulfoxide was added, and the mixture was stirred until bubbles were rare, followed by the addition of N,N'-di(2-morpholinoethyl)oxalamide (0.2mmol) and CuTc (0.2mmol), and the mixture was stirred until bubbles were rare, and finally chlorobenzene (1mmol) was added, the mixture was sealed, removed from the glove box, and placed in an oil bath at 140°C for 12h. After the reaction was completed, the mixture was extracted with ethyl acetate and saturated brine, the organic phase was collected, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain a colorless transparent oil with a yield of 61%. The NMR spectrum of compound (5) is shown in FIG. Figure 3 and 4 As shown:

[0063] HRMS-ESI(m / z)calcd for C 14 H 14 NO(M+H):212.1075,found:212.1073

[0064] 1 H NMR (400MHz, CDCl3) δ7.31–7.28(m,2H),7.20–7.18(m,2H),7.16–7.08(m,4H),7.03–6.99(m,2H),3.47(s,3H). 13 C NMR (101MHz, CDCl3) δ170.59,144.88,135.95,129.36,128.70,127.72,126.68,38.37.

[0065] Comparative Example 2

[0066] In 2021, Vito Capriati's research group used CuI to catalyze the CN coupling reaction of iodobenzene and N-methylbenzamide under the promotion of the ligand ethylenediamine, and obtained a 65% yield after separation and purification. Although the yield of the product obtained in this scheme is slightly higher, the ligand is only suitable for promoting more active and expensive aryl iodine compounds, and is not suitable for less active and less expensive aryl bromide or chlorine compounds.

[0067] Example 4 Synthesis of N-benzyl-N-(4-methoxyphenyl)benzamide

[0068]

[0069] In a glove box, N-benzylbenzamide (1.2mmol) and NaH (1.5mmol) were mixed, 1mL of ultra-dry dimethyl sulfoxide was added, and the mixture was stirred until bubbles were scarce, followed by the addition of N,N'-di(2-morpholinoethyl)oxalamide (0.2mmol) and CuTc (0.2mmol), and the mixture was stirred until bubbles were scarce, and finally 4-methoxybromobenzene (1mmol) was added, the mixture was sealed, removed from the glove box, and placed in an oil bath at 100°C for reaction for 24h. After the reaction was completed, the mixture was extracted with ethyl acetate and saturated brine, the organic phase was collected, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain a yellow transparent oil with a yield of 63%. The NMR spectrum of compound (8) is shown in FIG. Figure 5 and 6 As shown:

[0070] HRMS-ESI(m / z)calcd for C 21 H 20 NO2(M+H):318.1494,found:318.1493

[0071] 1 H NMR (400MHz, CDCl3) δ7.35–7.24(m,7H),7.24–7.23(m,1H),7.23–7.16(m,2H),7.13( d,J=6.8Hz,2H),6.79(d,J=8.4Hz,2H),6.66–6.58(m,2H),5.08(s,2H),3.66(s,3H). 13 C NMR (101MHz, CDCl3) δ170.62,157.97,137.63,136.20,129.47,128.97,128.70,128.61,128.49,127.74,127.38,114.15,55.28,53.97.

[0072] Comparative Example 3

[0073] In 1956, BILLMAN et al. used N-benzyl-p-aminoanisole and benzoyl chloride to prepare the corresponding tertiary amide by heating and reflux in an ethanol solution. Although this method is simpler to operate, N-benzyl-p-aminoanisole is expensive, which greatly increases the reaction cost. Benzoyl chloride reacts with moisture in the atmospheric environment, and has high requirements for the reaction solvent and air humidity.

[0074] It can be seen that the final yield obtained by the technical solution of the present application is not much different from that of the prior art, but due to the use of N,N'-di(2-morpholineethyl)oxalamide and CuTc catalyst, the cost is greatly reduced and the production efficiency is greatly improved, which is a significant improvement over the prior art.

[0075] The above embodiment is one of the specific implementation modes selected by the present invention. The common changes and substitutions made by those skilled in the art within the scope of this technical solution should be included in the protection scope of the present invention.

Claims

1. Application of N,N'-di(2-morpholinoethyl)oxalamide as a CuTc catalyst ligand in the synthesis of non-cyclic tertiary amides, characterized in that: The structural formula of N,N'-di(2-morpholinoethyl)oxalamide is as follows: ； The structure of the non-cyclic tertiary amide is as follows: or .

2. A method for synthesizing a non-cyclic tertiary amide, characterized in that: The specific steps are as follows: N,N'-di(2-morpholinoethyl)oxalamide promotes the coupling reaction of non-cyclic secondary amide and aryl halide compound catalyzed by CuTc in ultra-dry dimethyl sulfoxide solution at 60-140°C, and the target product is separated by column chromatography; wherein the structural formula of N,N'-di(2-morpholinoethyl)oxalamide is as follows: ； The structure of the target product non-cyclic tertiary amide is as follows: or ; The non-cyclic secondary amide structure used is as follows: ； The structural formula of the aryl halide compound used is as follows: or .

3. The method for synthesizing the non-cyclic tertiary amide according to claim 2, characterized in that: The specific steps are as follows: the non-cyclic secondary amide and NaH are placed in a pressure-resistant reaction bottle, 1 mL of dimethyl sulfoxide is added, and the mixture is stirred thoroughly until bubbles become scarce, then N,N'-di(2-morpholinoethyl)oxalamide and CuTc are added and stirred thoroughly until bubbles become scarce, and finally an aromatic halide compound is added, the mixture is sealed, removed from the glove box, and placed in an oil bath at 60-140°C for reaction for 12-24 h; after the reaction is completed, the mixture is extracted with saturated brine and ethyl acetate, the organic phase is collected, dried over anhydrous sodium sulfate, and separated by column chromatography to obtain pure non-cyclic tertiary amide.

4. The method for synthesizing the non-cyclic tertiary amide according to claim 3, characterized in that: The molar ratio of NaH to the non-cyclic secondary amide is in the range of 1-2.5:1; The ratio of the non-cyclic secondary amide to dimethyl sulfoxide is 1-3 ml of dimethyl sulfoxide for 1 mmol of the non-cyclic secondary amide; The ratio of N,N'-di(2-morpholinoethyl)oxalamide as a promoter to the non-cyclic secondary amide is 0.05-0.3:1; The molar ratio of N,N'-di(2-morpholinoethyl)oxalamide to CuTc is in the range of 1-2:1; The molar ratio of the aryl halide compound to the non-cyclic secondary amide is in the range of 1-1.5:

1.

5. The method for synthesizing the non-cyclic tertiary amide according to claim 3, characterized in that: When the reaction temperature is 100 ℃ and the reaction time is 24 h, the corresponding aryl halide compound is a bromide with slightly lower activity; when the reaction temperature is 60 ℃ and the reaction time is 18 h, the corresponding aryl halide compound is an iodide with higher activity; when the reaction temperature is 140 ℃ and the reaction time is 12 h, the corresponding aryl halide compound is a chloride with the lowest activity.

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