Multiphase preparation method of glycine ester derivative

Abstract

The invention belongs to the technical field of fine chemicals and related chemistry, and discloses a heterogeneous preparation method of a glycine ester derivative, the method uses monatomic iron as a catalyst, the reaction condition is mild, the selectivity is high, the reaction system is simple, the substrate compatibility is good, the highest yield can reach more than 95%, and the catalyst has good stability and can be recycled. Amine derivatives and diazonium derivatives are used as raw materials, under the inert gas condition, under the action of a monatomic iron catalyst, in an anhydrous organic solvent, reaction is carried out for 12 hours at room temperature, and the corresponding glycine ester compound is obtained, has wide application and has an important position in drug design and drug synthesis.

Description

Technical Field

[0001] The invention belongs to the field of fine chemicals and related chemical technologies, and provides a multiphase preparation method for glycine ester derivatives. Background Art

[0002] Glycine ester derivatives play a critical role in many fields such as medicine, agriculture and organic chemistry due to their excellent biological activity. However, the traditional method for preparing glycine ester mainly relies on the esterification reaction of glycine, but this method has limitations, such as the reversibility of the esterification reaction, which makes it difficult to carry out the reaction to the end, the narrow scalability of the substrate limits the diversity of the products, and the low reaction conversion rate. These problems have seriously restricted the widespread application of traditional synthesis methods.

[0003] In recent years, transition metal catalysis has gradually become an effective way to prepare glycine ester compounds due to its advantages such as high efficiency, high selectivity and relatively mild reaction conditions. However, in the process of homogeneous catalytic conversion, the catalyst is difficult to recycle and has poor stability, which greatly limits the prospects of homogeneous catalysis in industrial applications.

[0004] Since 2015, methods for synthesizing glycine ester compounds based on heterogeneous catalytic nitrogen-hydrogen bond insertion reactions of diazo compounds have been reported one after another (ACS Catal., 2015, 5, 350-355; Chem. Sci., 2015, 6, 1510-1515; J. Mol. Catal. A.: Chem., 2016, 417, 10-18). Although these methods have solved the problem of catalyst recycling to a certain extent, there are still many problems to be solved, such as complex catalyst preparation process, harsh reaction conditions, low catalytic efficiency and poor reaction selectivity, which still restrict the further development and application of this method.

[0005] As an emerging catalytic material, single-atom catalysts involve single and isolated metal atoms stably anchored on appropriate carriers. Their high atomic utilization and high activity make them one of the most dynamic research frontiers in the field of heterogeneous catalysis in recent years. At present, two types of single-atom catalyzed glycine ester synthesis methods have been reported, using single-atom iridium catalysts (ACS Catal., 2024, 14, 4690-4698) and single-atom rhodium catalysts (J.Am.Chem.Soc., 2024, 146, 10847-10856). However, both of these catalysts are precious metal catalysts with high costs, so it is particularly necessary to develop relatively low-cost and more efficient alternatives. Summary of the invention

[0006] The present invention provides a heterogeneous preparation method of glycine ester derivatives. This method uses single-atom iron as a catalyst, with mild reaction conditions, high selectivity, a maximum yield of over 95%, good catalyst stability, and recyclability.

[0007] The technical solution of the present invention:

[0008] A heterogeneous preparation method of glycine ester derivatives, using amine derivatives and diazo ester derivatives as raw materials. Under an inert gas condition, in the presence of a single-atom iron catalyst, in an anhydrous organic solvent, react at room temperature for 12 hours to obtain the corresponding glycine ester derivatives. The synthetic route is as follows:

[0009]

[0010] Among them,

[0011] R 1 、R 2 are selected from a hydrogen atom, an alkyl group, and an aryl group;

[0012] R 3 is selected from an alkyl group and an aryl group;

[0013] The molar ratio of the amine derivative to the diazo ester derivative is 1:2;

[0014] The feeding ratio of the amine compound to the catalyst is 0.1 mmol:1 mg;

[0015] The feeding ratio of the diazo ester derivative to the catalyst is 0.2 mmol:1 mg;

[0016] The molar concentration of the amine derivative in the organic solvent is 0.1 mmol / mL;

[0017] The molar concentration of the diazo ester derivative in the anhydrous organic solvent is 0.2 mmol / mL;

[0018] The anhydrous organic solvent is one or more of dichloromethane, diethyl ether, ethanol, toluene, acetonitrile, dimethyl sulfoxide, tetrahydrofuran, N-methylpyrrolidone, etc., preferably dichloromethane, diethyl ether, ethanol, and tetrahydrofuran;

[0019] The separation method is column chromatography.

[0020] When using column chromatography to separate the product, silica gel can be used as the stationary phase, and the eluent is generally a mixed solvent of polar and non-polar solvents, such as ethyl acetate - petroleum ether, ethyl acetate - n-hexane, dichloromethane - petroleum ether, methanol - petroleum ether.

[0021] Proton nuclear magnetic resonance spectroscopy and carbon nuclear magnetic resonance spectroscopy are used for qualitative analysis, and dibromomethane is used as an internal standard for quantitative analysis.

[0022] Advantages of the present invention: The synthesis method of this application uses a cheap single-atom iron catalyst to successfully achieve the nitrogen-hydrogen bond insertion reaction under mild conditions. The reaction system is simple, the substrate compatibility is good, the product yield is high, and it has good application value. The catalyst has good repeatability and high atomic utilization rate. The obtained glycine ester compounds have a wide range of uses and play an important role in drug design and drug synthesis (Org. Lett., 2020, 22, 5005-5008; Chem. Commun., 2020, 56, 9691-9694). Description of the Drawings

[0023] Figure 1 is the 1 1H NMR spectrum of ethyl N-methyl-N-phenylglycinate in Example 1.

[0024] Figure 2 is the 13 13C NMR spectrum of ethyl N-methyl-N-phenylglycinate in Example 1.

[0025] Figure 3 is the 1 1H NMR spectrum of ethyl N-ethyl-N-phenylglycinate in Example 2.

[0026] Figure 4 is the 13 13C NMR spectrum of ethyl N-ethyl-N-phenylglycinate in Example 2.

[0027] Figure 5 is the 1 1H NMR spectrum of ethyl (2-bromophenyl)glycinate in Example 3.

[0028] Figure 6 is the 13 13C NMR spectrum of ethyl (2-bromophenyl)glycinate in Example 3.

[0029] Figure 7 is the 1 1H NMR spectrum of ethyl phenylglycinate in Example 4.

[0030] Figure 8 is the 13 13C NMR spectrum of ethyl phenylglycinate in Example 4.

[0031] Figure 9 is the 1 1H NMR spectrum of tert-butyl N-methyl-N-phenylglycinate in Example 5.

[0032] Figure 10 is the 13 13C NMR spectrum of tert-butyl N-methyl-N-phenylglycinate in Example 5.

[0033] Figure 11 is the 1 1H NMR spectrum of N-methyl-N-phenylglycine benzyl ester in Example 6.

[0034] Figure 12 is the 13 13C NMR spectrum of N-methyl-N-phenylglycine benzyl ester in Example 6.

[0035] Figure 13 is the 1 1H NMR spectrum of cinnamoyl N-methyl-N-phenylglycine ester in Example 7.

[0036] Figure 14 is the 13 13C NMR spectrum of cinnamoyl N-methyl-N-phenylglycine ester in Example 7.

[0037] Figure 15 is the 1 1H NMR spectrum of phenyl N-methyl-N-phenylglycine ester in Example 8.

[0038] Figure 16 is the 13 13C NMR spectrum of phenyl N-methyl-N-phenylglycine ester in Example 8.

[0039] Figure 17 is the EDS elemental mapping of the catalyst, where (a) is the mapping of the C element corresponding to the single-atom Fe catalyst, (b) is the mapping of the Fe element corresponding to the single-atom Fe catalyst, (c) is the mapping of the N element corresponding to the single-atom Fe catalyst, and (d) is the HAADF-STEM image of the single-atom Fe catalyst.

[0040] Figure 18 is the recycling experiment of the single-atom Fe catalyst for the N-H bond insertion reaction. Detailed Embodiments

[0041] The following further illustrates the detailed embodiments of the present invention in conjunction with the accompanying drawings and technical solutions.

[0042] Example 1: Synthesis of Ethyl N-methyl-N-phenylglycinate

[0043] In the glove box, N-methylaniline (21.4 mg, 0.2 mmol), ethyl diazoacetate (45.6 mg, 0.4 mmol), and a catalyst (2.0 mg) were successively added to a 25 mL Schlenk flask. After adding 2.0 mL of anhydrous tetrahydrofuran to dissolve, the Schlenk flask was tightened and reacted at room temperature for 12 h. After the reaction was completed, the product was separated by column chromatography. 37.1 mg of ethyl N-methyl-N-phenylglycinate was obtained, with a yield of 96%.

[0044] ethyl N-methyl-N-phenylglycinate

[0045] Yellow oily liquid; 1 H NMR (400 MHz, Chloroform-d) δ 7.33 - 7.08 (m, 2H), 6.73 (t, J = 7.3 Hz, 1H), 6.68 (d, J = 8.2 Hz, 2H), 4.16 (q, J = 7.2 Hz, 2H), 4.04 (s, 2H), 3.05 (s, 3H), 1.22 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 171.1, 149.0, 129.2, 117.4, 112.4, 77.5, 77.1, 76.8, 60.9, 54.6, 39.5, 14.3.

[0046] Example 2: Synthesis of ethyl N-ethyl-N-phenylglycinate

[0047] In the glove box, N-ethyl-N-aniline (24.2 mg, 0.2 mmol), ethyl diazoacetate (45.6 mg, 0.4 mmol), and a catalyst (2.0 mg) were successively added to a 25 mL Schlenk flask. After adding 2.0 mL of anhydrous dichloromethane to dissolve, the Schlenk flask was tightened and reacted at room temperature for 12 h. After the reaction was completed, the product was separated by column chromatography. 37.3 mg of ethyl N-ethyl-N-phenylglycinate was obtained, with a yield of 90%.

[0048] ethyl N-ethyl-N-phenylglycinate

[0049] Yellow oily liquid; 11H NMR (400 MHz, Chloroform-d) δ 7.25 - 7.17 (m, 2H), 6.70 (t, J = 7.3 Hz, 1H), 6.64 (d, J = 7.9 Hz, 2H), 4.19 (q, J = 7.1 Hz, 2H), 4.00 (s, 2H), 3.46 (q, J = 7.1 Hz, 2H), 1.25 (t, J = 7.1 Hz, 3H), 1.20 (t, J = 7.1 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 170.7, 148.7, 131.3, 117.4, 111.4, 77.4, 77.1, 76.8, 60.6 51.8, 45.2, 15.6, 12.5.

[0050] Example 3: Synthesis of Ethyl (2-bromophenyl)glycinate

[0051] In a glove box, o-bromoaniline (34.4 mg, 0.2 mmol), ethyl diazoacetate (45.6 mg, 0.4 mmol), and a catalyst (2.0 mg) were successively added to a 25 mL Schlenk flask. After dissolving in 2.0 mL of anhydrous ether, the Schlenk flask was tightened and reacted at room temperature for 12 h. After the reaction was completed, the product was separated by column chromatography. 47.8 mg of ethyl (2-bromophenyl)glycinate was obtained, with a yield of 93%.

[0052] Ethyl (2-bromophenyl)glycinate

[0053] Yellow oily liquid; 1 1H NMR (400 MHz, Chloroform-d) δ 7.45 (dd, J = 7.9, 1.5 Hz, 1H), 7.18 (td, J = 7.7, 1.5 Hz, 1H), 6.62 (td, J = 7.6, 1.5 Hz, 1H), 6.51 (dd, J = 8.1, 1.5 Hz, 1H), 4.97 (s, 1H), 4.26 (q, J = 7.1 Hz, 2H), 3.94 (d, J = 5.3 Hz, 2H), 1.31 (t, J = 7.1 Hz, 3H). 13 13C NMR (101 MHz, CDCl3) δ 170.5, 144.0, 132.6, 128.5, 118.6, 111.7, 110.0, 77.4, 77.0, 76.7, 61.5, 45.7, 14.2.

[0054] Example 4: Ethyl phenylglycinate

[0055] In the glove box, aniline (18.6 mg, 0.2 mmol), ethyl diazoacetate (45.6 mg, 0.4 mmol), and a catalyst (2.0 mg) were successively added to a 25 mL Schlenk flask. After adding 2.0 mL of anhydrous ethanol to dissolve, the Schlenk flask was tightened and reacted at room temperature for 12 h. After the reaction, the product was separated by column chromatography. 31.5 mg of ethyl phenylglycinate was obtained with a yield of 88%.

[0056] Ethyl phenylglycinate

[0057] Yellow oily liquid; 1 H NMR (400 MHz, Chloroform-d) δ 7.19 (t, J = 7.7 Hz, 2H), 6.75 (t, J = 7.0 Hz, 1H), 6.61 (d, J = 8.0 Hz, 2H), 4.24 (q, J = 7.1 Hz, 2H), 3.90 (s, 2H), 1.30 (t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 171.2, 147.6, 129.4, 118.2, 113.0, 77.4 77.0, 76.7, 61.3, 45.9, 14.2.

[0058] Example 5: Synthesis of tert-butyl N-methyl-N-phenylglycinate

[0059] In the glove box, N-methylaniline (21.4 mg, 0.2 mmol), tert-butyl diazoacetate (56.8 mg, 0.4 mmol), and a catalyst (2.0 mg) were successively added to a 25 mL Schlenk flask. After adding 2.0 mL of anhydrous tetrahydrofuran to dissolve, the Schlenk flask was tightened and reacted at room temperature for 12 h. After the reaction, the product was separated by column chromatography. 37.6 mg of tert-butyl N-methyl-N-phenylglycinate was obtained with a yield of 85%.

[0060] tert-butyl N-methyl-N-phenylglycinate

[0061] Colorless oily liquid; 1 H NMR (400 MHz, Chloroform-d) δ 7.15 (t, J = 7.9 Hz, 2H), 6.66 (t, J = 7.3 Hz, 1H), 6.61 (d, J = 8.1 Hz, 2H), 3.88 (s, 2H), 2.98 (s, 3H), 1.34 (s, 9H). 1313C NMR (101 MHz, CDCl3) δ 170.3, 149.0, 129.1, 117.2, 112.3, 81.5, 77.4, 77.1, 76.7, 55.4, 39.7, 28.1.

[0062] Example 6: Synthesis of Benzyl N-Methyl-N-phenylglycinate

[0063] The operation was the same as in Example 5. Benzyl N-Methyl-N-phenylglycinate (46.4 mg, yield 91%) was obtained by reacting N-methylaniline (21.4 mg, 0.2 mmol) with benzyl 2-diazoacetate (70.4 mg, 0.4 mmol) for 12 hours.

[0064] Benzyl N-Methyl-N-phenylglycinate

[0065] Colorless solid; 1 1H NMR (400 MHz, Chloroform-d) δ 7.38 - 7.25 (m, 7H), 6.80 (td, J = 7.3, 1.1 Hz, 1H), 6.78 - 6.70 (m, 2H), 5.19 (s, 2H), 4.15 (s, 2H), 3.11 (s, 3H). 13 13C NMR (101 MHz, CDCl3) δ 170.9, 148.8, 135.6, 129.3, 128.6, 128.3, 128.2, 117.6, 112.5, 77.4, 77.1, 76.7, 66.6, 54.6, 39.6.

[0066] Example 7: Synthesis of Cinnamoyl N-Methyl-N-phenylglycinate

[0067] The operation was the same as in Example 5. Cinnamoyl N-Methyl-N-phenylglycinate (48.3 mg, yield 86%) was obtained by reacting N-methylaniline (21.4 mg, 0.2 mmol) with cinnamyl 2-diazoacetate (80.8 mg, 0.4 mmol) for 12 hours.

[0068] Cinnamoyl N-Methyl-N-phenylglycinate

[0069] Colorless oily liquid; 1 1H NMR (400 MHz, Chloroform-d) δ 7.42 - 7.15 (m, 7H), 6.79 - 6.68 (m, 3H), 6.59 (d, J = 15.7 Hz, 1H), 6.23 (dt, J = 15.9, 6.3 Hz, 1H), 4.77 (d, J = 6.3 Hz, 2H), 4.11 (s, 2H), 3.08 (s, 3H).13 C NMR (101 MHz, CDCl3) δ 170.9, 148.9, 136.15, 134.4, 129.3, 128.6, 128.2, 126.7, 122.8, 117.5, 112.4, 77.4, 77.1, 76.7, 65.4, 54.6, 39.6.

[0070] Example 8: Synthesis of Phenyl N-Methyl-N-phenylglycinate

[0071] The operation was the same as in Example 5. Phenyl N-Methyl-N-phenylglycinate (45.3 mg, yield 94%) was obtained by reacting N-methylaniline (21.4 mg, 0.2 mmol) with phenyl 2-diazoacetate (64.8 mg, 0.4 mmol) for 12 hours.

[0072] Phenyl N-Methyl-N-phenylglycinate

[0073] Colorless solid; 1 H NMR (400 MHz, Chloroform-d) δ 7.39 - 7.16 (m, 5H), 7.03 (dd, J = 8.6, 1.2 Hz, 2H), 6.82 - 6.75 (m, 3H), 4.31 (s, 2H), 3.15 (s, 3H). 13 C NMR (101 MHz, CDCl3) δ 169.7, 150.5, 148.8, 129.5, 129.3, 126.0, 121.4, 117.7, 112.5, 77.4, 77.1, 76.7, 54.8, 39.7.

[0074] Results of catalyst recycling experiment:

[0075] The stability of the catalyst was investigated by cyclic testing. Figure 18 The results showed that the yield was still as high as 94.5% after five cycles, indicating the high stability of the catalyst.

Claims

1. A multiphase preparation method of a glycine ester derivative, characterized in that: Using amine derivatives and diazo ester derivatives as raw materials, in anhydrous organic solvents, under inert gas conditions, in the presence of a single-atom iron catalyst, the reaction is carried out at room temperature for 12 hours to obtain the corresponding glycine ester derivatives. The synthetic route is as follows: in, R 1 , R 2 is selected from the group consisting of a hydrogen atom, an alkyl group and an aryl group; R 3 Selected from alkyl and aryl.

2. The multiphase preparation method according to claim 1, characterized in that: The molar ratio of the amine derivative to the diazoester derivative is 1:2; The feed ratio of amine compound to catalyst is 0.1mmol:1mg; The feed ratio of the diazo ester derivative to the catalyst is 0.2 mmol:1 mg.

3. The multiphase preparation method according to claim 1, characterized in that: The molar concentration of the amine derivatives in the organic solvent was 0.1 mmol / mL; The molar concentration of the diazo ester derivative in the anhydrous organic solvent is 0.2 mmol / mL.

4. The multiphase preparation method according to claim 1, characterized in that: The anhydrous organic solvent is one or a mixture of two or more of dichloromethane, ether, ethanol, toluene, acetonitrile, dimethyl sulfoxide, tetrahydrofuran and N-methylpyrrolidone.

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