A preparation method of α-hydroxy-γ-aminobutyric acid compounds

Abstract

The present invention belongs to the technical field of organic synthesis and discloses a method for preparing α-hydroxy-γ-aminobutyric acid compounds. The method comprises dispersing nitroaromatic hydrocarbons, acrylic acid, a carbon source, a hydrogen source, a catalyst, and an alkaline additive in an organic solvent and reacting the mixture in a protective atmosphere to obtain α-hydroxy-γ-aminobutyric acid compounds. The method of the present invention features readily available and inexpensive raw materials, good functional group compatibility, high atom economy, a recyclable catalyst, simple preparation, and mild reaction conditions. The compounds prepared by the present invention have broad prospects for industrial application.

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and particularly relates to a method for preparing an α-hydroxy-γ-aminobutyric acid compound. Background Art

[0002] α-Hydroxy-γ-aminobutyric acid (α-Hydroxy-γ-aminobutyric acid) is the preferred side chain for the semi-synthesis of aminoglycoside antibiotics. Most of these antibiotics exhibit enhanced antimicrobial activity when attached to α-Hydroxy-γ-aminobutyric acid at appropriate sites, with particularly significant increases against drug-resistant bacteria. For example, amikacin, a semi-synthetic derivative of kanamycin, exhibits enhanced activity against Enterobacteriaceae and Pseudomonas. However, due to chemical and regioselectivity, as well as the often difficult preparation of synthetic precursors, the applicability of substrates is significantly limited. Under these circumstances, the synthesis of α-Hydroxy-γ-aminobutyric acid compounds inevitably results in waste of resources, environmental pollution, and other issues, failing to meet practical production needs.

[0003] Therefore, it is necessary to develop a simple method to efficiently construct α-hydroxy-γ-aminobutyric acid from cheap, readily available and non-prepared starting materials. Summary of the Invention

[0004] In order to overcome the shortcomings and deficiencies of the prior art, the object of the present invention is to provide a method for preparing α-hydroxy-γ-aminobutyric acid compounds.

[0005] The purpose of the present invention is achieved through the following technical solutions.

[0006] A method for preparing an α-hydroxy-γ-aminobutyric acid compound comprises the following steps: dispersing nitroaromatic hydrocarbon, acrylic acid, a carbon source, a hydrogen source, a catalyst and an alkaline additive in an organic solvent, placing the mixture in a protective atmosphere for reaction, and obtaining an α-hydroxy-γ-aminobutyric acid compound having the structure

[0007] The nitroaromatic hydrocarbon is Where R 1 is one or two of hydrogen, methyl, ethyl, methoxy, halogen, carboxyl, trifluoromethyl, carbonyl, cyano, and aldehyde; the acrylic acid is The carbon source is at least one of formaldehyde and paraformaldehyde; the hydrogen source is at least one of formic acid and phenylsilane.

[0008] Preferably, the nitroaromatic hydrocarbon is one of nitrobenzene, p-ethylnitrobenzene, p-fluoronitrobenzene, m-nitrobenzenenitrile, m-nitrobenzaldehyde, and 2-bromo-4-nitroanisole.

[0009] Preferably, the carbon source is paraformaldehyde.

[0010] Preferably, the hydrogen source is formic acid.

[0011] The molar ratio of the nitroaromatic hydrocarbon, acrylic acid, carbon source and hydrogen source is (1.1-1.6):1:(1.3-1.6):(6-7). Preferably, the molar ratio of the nitroaromatic hydrocarbon, acrylic acid, carbon source and hydrogen source is 1.3-1.6:1:1.3-1.6:6-7.

[0012] Preferably, the catalyst is a heterogeneous cobalt catalyst.

[0013] Further preferably, the catalyst is a cobalt-nitrogen co-doped porous carbon material.

[0014] Preferably, the cobalt-nitrogen co-doped porous carbon material is prepared by the following method: dispersing cobalt acetate, 5,6-diamino-1,10-phenanthroline and carbon powder in an organic solvent, then separating the solid and pyrolyzing it at 700°C to 900°C for 2h to 3h to obtain the cobalt-nitrogen co-doped porous carbon material.

[0015] In the preparation of the cobalt-nitrogen co-doped porous carbon material, the mass ratio of the cobalt acetate, 5,6-diamino-1,10-phenanthroline, and carbon powder is 0.1-0.5:0.3-0.6:1.

[0016] In the preparation of the cobalt-nitrogen co-doped porous carbon material, the organic solvent is ethanol.

[0017] The molar ratio of cobalt to acrylic acid in the catalyst is 0.04-0.06:1.

[0018] The alkaline additive is at least one of pyridine, 1,8-diazabicycloundec-7-ene, and triethylamine, preferably pyridine.

[0019] The molar ratio of the alkaline additive to the nitroaromatic hydrocarbon is 0.2-0.6:1.

[0020] The solvent is at least one of methanol, ethanol, toluene, tetrahydrofuran and acetonitrile, preferably tetrahydrofuran.

[0021] The protective atmosphere is a nitrogen atmosphere or an argon atmosphere.

[0022] The reaction is carried out at 80°C to 100°C.

[0023] The reaction time is 16 h to 20 h.

[0024] Preferably, after the reaction is completed, the reaction product is purified by column chromatography.

[0025] The eluent used in the column chromatography purification is prepared by mixing petroleum ether, ethyl acetate and methanol in a volume ratio of 1-10:2-4:1.

[0026] The equation for the reaction is:

[0027]

[0028] The present invention provides the following beneficial effects: The method for synthesizing α-hydroxy-γ-aminobutyric acid has the advantages of readily available and inexpensive raw materials, good functional group compatibility, high atom economy, recyclable catalyst, simple preparation, and mild reaction conditions. Notably, the α-hydroxy-γ-aminobutyric acid prepared by this reaction can be converted into a pharmaceutically valuable product through simple operations, thus possessing broad prospects for industrial application.

[0029] Specifically:

[0030] 1) The raw materials of the present invention are nitroaromatic hydrocarbons, acrylic acid, formaldehyde / paraformaldehyde (carbon source), and formic acid (hydrogen source). The reaction is a three-molecule coupling reaction of nitroaromatic hydrocarbons, paraformaldehyde, and acrylic acid carried out via a heterogeneous cobalt catalyst to produce α-hydroxy-γ-aminobutyric acid compounds in a single step. The reaction is simple to operate, has mild reaction conditions, and the catalyst is reusable, demonstrating its potential for industrial production.

[0031] 2) The raw materials of the present invention do not need to carry pre-prepared functional groups and do not require complicated pretreatment. The raw materials are easy to obtain and suitable for industrial large-scale production;

[0032] 3) The synthesis of the α-hydroxy-γ-aminobutyric acid compounds of the present invention does not require complicated post-processing steps and can be obtained in one step, and the separation is simple;

[0033] 4) The substrate compatibility of the present invention is good, and the corresponding products can be obtained in moderate to excellent yields for both electron-rich and electron-donating groups. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 The α-hydroxy-γ-aminobutyric acid compound prepared in Example 1 1 H NMR spectrum;

[0035] Figure 2 The α-hydroxy-γ-aminobutyric acid compound prepared in Example 1 13 C NMR spectrum;

[0036] Figure 3 The α-hydroxy-γ-aminobutyric acid compound prepared in Example 2 1 H NMR spectrum;

[0037] Figure 4 The α-hydroxy-γ-aminobutyric acid compound prepared in Example 2 13 C NMR spectrum;

[0038] Figure 5 The α-hydroxy-γ-aminobutyric acid compound prepared in Example 3 1 H NMR spectrum;

[0039] Figure 6 The α-hydroxy-γ-aminobutyric acid compound prepared in Example 3 13 C NMR spectrum;

[0040] Figure 7 The α-hydroxy-γ-aminobutyric acid compound prepared in Example 3 19 F NMR spectrum;

[0041] Figure 8 The α-hydroxy-γ-aminobutyric acid compound prepared in Example 4 1 H NMR spectrum;

[0042] Figure 9 The α-hydroxy-γ-aminobutyric acid compound prepared in Example 4 13 C NMR spectrum;

[0043] Figure 10 The α-hydroxy-γ-aminobutyric acid compound prepared in Example 5 1 H NMR spectrum;

[0044] Figure 11 The α-hydroxy-γ-aminobutyric acid compound prepared in Example 5 13 C NMR spectrum;

[0045] Figure 12 The α-hydroxy-γ-aminobutyric acid compound prepared in Example 6 1 H NMR spectrum;

[0046] Figure 13 The α-hydroxy-γ-aminobutyric acid compound prepared in Example 6 13 C NMR spectrum. DETAILED DESCRIPTION

[0047] The present invention will be further explained and illustrated below with reference to specific examples, but the embodiments of the present invention are not limited thereto.

[0048] The cobalt-nitrogen co-doped porous carbon materials in Examples 1 to 13 were prepared by the following method: 125 mg of cobalt acetate, 316 mg of 5,6-diamino-1,10-phenanthroline and 700 mg of carbon powder were added to 40 mL of ethanol, stirred for 4 h, and then distilled under reduced pressure and dried in a vacuum oven at 80°C overnight, and then pyrolyzed at 800°C for 2 h to obtain cobalt-nitrogen co-doped porous carbon materials (the mass fraction of cobalt is 2.5%).

[0049] Example 1:

[0050] A method for preparing an α-hydroxy-γ-aminobutyric acid compound comprises the following steps:

[0051] 0.38 mmol of nitrobenzene, 0.38 mmol of paraformaldehyde, 0.25 mmol of acrylic acid, 1.5 mmol of formic acid, 30 mg of cobalt-nitrogen co-doped porous carbon material and 0.1 mmol of pyridine were stirred and dispersed in 2 mL of freshly distilled tetrahydrofuran, then placed in a nitrogen atmosphere at 90 ° C for 18 hours, naturally cooled to room temperature, and concentrated in vacuo. The crude product obtained by concentration was purified by column chromatography. The eluent used for column chromatography purification was prepared by mixing petroleum ether, ethyl acetate and methanol in a volume ratio of 10:2:1 to obtain an aminobutyric acid compound (white solid, yield 66%).

[0052] The nuclear magnetic resonance hydrogen spectrum of the α-hydroxy-γ-aminobutyric acid compound of this example ( 1 H NMR) and carbon nuclear magnetic resonance spectra ( 13 C NMR) Figure 1 and Figure 2 shown.

[0053] Spectral analysis:

[0054] 1 H NMR (500MHz, Chloroform-d): δ7.63 (d, J=10.0Hz, 2H), 7.38 (t, J=5.0Hz, 2H), 7.18 (t, J=5 .0Hz, 1H), 4.52 (t, J=5.0Hz, 1H), 3.82-3.73 (m, 2H), 2.61-2.55 (m, 1H), 2.15-2.07 (m, 1H).

[0055] 13 C NMR (126MHz, Chloroform-d): δ 174.6, 139.0, 129.1, 125.3, 119.9, 70.8, 44.7, 27.7.

[0056] HRMS(ESI):Calcd.for C 10 H13 NO3[MH] + :194.0895; found:194.0823.

[0057] In summary, the structural formula of the α-hydroxy-γ-aminobutyric acid compound prepared in this example is:

[0058]

[0059] Example 2:

[0060] A method for preparing an α-hydroxy-γ-aminobutyric acid compound comprises the following steps:

[0061] 0.38 mmol of p-ethylnitrobenzene, 0.38 mmol of paraformaldehyde, 0.25 mmol of acrylic acid, 1.5 mmol of formic acid, 30 mg of cobalt-nitrogen co-doped porous carbon material and 0.1 mmol of pyridine were stirred and dispersed in 2 mL of freshly distilled tetrahydrofuran, and then placed in a nitrogen atmosphere at 90 ° C for 18 hours. The reaction was naturally cooled to room temperature and concentrated in vacuo. The crude product obtained by concentration was purified by column chromatography. The eluent used for column chromatography purification was prepared by mixing petroleum ether, ethyl acetate and methanol in a volume ratio of 10:2:1 to obtain an aminobutyric acid compound (white solid, yield 70%).

[0062] The 1H NMR spectrum of the α-hydroxy-γ-aminobutyric acid compounds of this example and 13 C NMR spectrum Figure 3 and Figure 4 shown.

[0063] Spectral analysis:

[0064] 1 H NMR (500MHz, Chloroform-d): δ7.52 (d, J=5.0Hz, 2H), 7.20 (d, J=10.0Hz, 2H), 4.50 (t, J=5.0Hz, 1H), 4.06 ( s, 1H), 3.80-3.73 (m, 2H), 2.65-2.61 (m, 2H), 2.60-2.54 (m, 1H), 2.14-2.06 (m, 1H), 1.22 (t, J=10.0Hz, 3H).

[0065] 13 C NMR (126MHz, Chloroform-d): δ1δ 174.3, 141.4, 136.7, 128.4, 120.1, 70.8, 44.9, 28.4, 27.8, 15.7.

[0066] HRMS(ESI):Calcd.for C 12 H 17 NO3[MH] + :222.1208; found:222.1136.

[0067] In summary, the structural formula of the α-hydroxy-γ-aminobutyric acid compound prepared in this example is:

[0068]

[0069] Example 3:

[0070] A method for preparing an α-hydroxy-γ-aminobutyric acid compound comprises the following steps:

[0071] 0.38 mmol of p-fluoronitrobenzene, 0.38 mmol of paraformaldehyde, 0.25 mmol of acrylic acid, 1.5 mmol of formic acid, 30 mg of cobalt-nitrogen co-doped porous carbon material and 0.1 mmol of pyridine were stirred and dispersed in 2 mL of freshly distilled tetrahydrofuran, and then placed in a nitrogen atmosphere at 90 ° C for 18 hours. The reaction was naturally cooled to room temperature and concentrated in vacuo. The crude product obtained by concentration was purified by column chromatography. The eluent used for column chromatography purification was prepared by mixing petroleum ether, ethyl acetate and methanol in a volume ratio of 10:2:1 to obtain an aminobutyric acid compound (brown solid, yield 78%).

[0072] The α-hydroxy-γ-aminobutyric acid compounds of this embodiment 1 H NMR spectrum, 13 C NMR spectra and 19 F NMR spectrum Figure 5 、 Figure 6 and Figure 7 shown.

[0073] Spectral analysis:

[0074] 1 H NMR (500MHz, Chloroform-d): δ7.54-7.51 (m, 2H), 7.00 (t, J=5.0Hz, 2H), 4.45 (t, J= 10.0Hz, 1H), 4.19 (s, 1H), 3.73-3.65 (m, 2H), 2.55-2.49 (m, 1H), 2.09-2.01 (m, 1H).

[0075] 13C NMR (126MHz, Chloroform-d): δ 174.5, 160.9, 159.0, 135.1, 121.7, 121.7, 115.9, 115.7, 70.7, 45.0, 27.7.

[0076] 19 F NMR (471MHz, Chloroform-d): δ-116.72.

[0077] HRMS(ESI):Calcd.for C 10 H 12 FNO3[MH] + :212.0801; found:212.0728.

[0078] In summary, the structural formula of the α-hydroxy-γ-aminobutyric acid compound prepared in this example is:

[0079]

[0080] Example 4:

[0081] A method for preparing an α-hydroxy-γ-aminobutyric acid compound comprises the following steps:

[0082] 0.38 mmol of m-nitrobenzonitrile, 0.38 mmol of paraformaldehyde, 0.25 mmol of acrylic acid, 1.5 mmol of formic acid, 30 mg of cobalt-nitrogen co-doped porous carbon material and 0.1 mmol of pyridine were stirred and dispersed in 2 mL of freshly distilled tetrahydrofuran, and then placed in a nitrogen atmosphere at 90 ° C for 18 hours. The reaction was naturally cooled to room temperature and concentrated in vacuo. The crude product obtained by concentration was purified by column chromatography. The eluent used for column chromatography purification was prepared by mixing petroleum ether, ethyl acetate and methanol in a volume ratio of 5:2:1 to obtain an aminobutyric acid compound (yellow solid, yield 42%).

[0083] The α-hydroxy-γ-aminobutyric acid compounds of this embodiment 1 H NMR spectra and 13 C NMR spectrum Figure 8 and Figure 9 shown.

[0084] Spectral analysis:

[0085] 1H NMR (500MHz, Chloroform-d): δ8.00 (s, 1H), 7.93-7.91 (m, 1H), 7.50-7.44 (m, 2 H), 4.55-4.52(m, 1H), 3.86-3.75(m, 2H), 2.67-2.62(m, 1H), 2.19-2.11(m, 1H).

[0086] 13 C NMR (126MHz, Chloroform-d): δ 174.9, 139.8, 130.0, 128.4, 123.5, 122.6, 118.5, 113.2, 70.7, 44.4, 27.5.

[0087] HRMS(ESI):Calcd.for C 11 H 12 N2O3[MH] + :219.0848; found:219.0075.

[0088] In summary, the structural formula of the α-hydroxy-γ-aminobutyric acid compound prepared in this example is:

[0089]

[0090] Example 5:

[0091] A method for preparing an α-hydroxy-γ-aminobutyric acid compound comprises the following steps:

[0092] 0.38 mmol of m-nitrobenzaldehyde, 0.38 mmol of paraformaldehyde, 0.25 mmol of acrylic acid, 1.5 mmol of formic acid, 30 mg of cobalt-nitrogen co-doped porous carbon material and 0.1 mmol of pyridine were stirred and dispersed in 2 mL of freshly distilled tetrahydrofuran, and then placed in a nitrogen atmosphere at 90 ° C for 18 hours. The reaction was naturally cooled to room temperature and concentrated in vacuo. The crude product obtained by concentration was purified by column chromatography. The eluent used for column chromatography purification was prepared by mixing petroleum ether, ethyl acetate and methanol in a volume ratio of 5:2:1 to obtain an aminobutyric acid compound (brown solid, yield 74%).

[0093] The α-hydroxy-γ-aminobutyric acid compounds of this embodiment 1 H NMR spectra and 13 C NMR spectrum Figure 10 and Figure 11 shown.

[0094] Spectral analysis:

[0095] 1H NMR (500MHz, Chloroform-d): δ9.98 (s, 1H), 8.04 (t, J=5.0Hz, 2H), 7.66 (d, J=10.0Hz, 1H), 7.52 (t, J=10 .0Hz, 1H), 4.88 (s, 1H), 4.55 (t, J=5.0Hz, 1H), 3.85-3.79 (m, 2H), 2.64-2.59 (m, 1H), 2.18-2.10 (m, 1H).

[0096] 13 C NMR (126MHz, Chloroform-d): δ 192.1, 175.4, 139.8, 137.0, 129.8, 126.6, 125.6, 119.7, 70.7, 44.7, 27.6.

[0097] HRMS(ESI):Calcd.for C 11 H 13 NO4[M+H] + :222.0845; found:222.0772.

[0098] In summary, the structural formula of the α-hydroxy-γ-aminobutyric acid compound prepared in this example is:

[0099]

[0100] Example 6:

[0101] A method for preparing an α-hydroxy-γ-aminobutyric acid compound comprises the following steps:

[0102] 0.38mmol 2-bromo-4-nitroanisole, 0.38mmol paraformaldehyde, 0.25mmol acrylic acid, 1.5mmol formic acid, 30mg cobalt-nitrogen co-doped porous carbon material and 0.1mmol pyridine were stirred and dispersed in 2mL freshly steamed tetrahydrofuran, then placed in a nitrogen atmosphere at 90°C for 18h, naturally cooled to room temperature, and concentrated in vacuo. The crude product obtained by concentration was purified by column chromatography. The eluent used for column chromatography purification was prepared by mixing petroleum ether, ethyl acetate and methanol in a volume ratio of 5:2:1 to obtain an aminobutyric acid compound (brown solid, yield 72%).

[0103] The α-hydroxy-γ-aminobutyric acid compounds of this embodiment 1 H NMR spectra and 13 C NMR spectrum Figure 12 and Figure 13 shown.

[0104] Spectral analysis:

[0105] 1 H NMR (500MHz, Chloroform-d): δ7.77 (s, 1H), 7.54 (d, J=10.0Hz, 1H), 6.85 (d, J=5.0Hz, 1H), 4.50 (t, J=10.0Hz, 1H), 4.40 (s, 1H), 3.85 (s, 3H), 3.74-3.65 (m, 2H), 2.58-2.52 (m, 1H), 2.13-2.02 (m, 1H).

[0106] 13 C NMR (126MHz, Chloroform-d): δ 174.5, 153.3, 132.9, 125.0, 120.4, 111.8, 111.6, 70.6, 56.5, 45.0, 27.6.

[0107] HRMS(ESI):Calcd for C 11 H 14 BrNO4[M+H] + : 304.0106; found: m / z 304.0179.

[0108] In summary, the structural formula of the α-hydroxy-γ-aminobutyric acid compound prepared in this example is:

[0109]

[0110] The above embodiments are preferred implementation modes of the present invention, but the implementation modes of the present invention are not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the spirit and principles of the present invention should be considered as equivalent replacement methods and are included in the scope of protection of the present invention.

Claims

1. A method for preparing an α-hydroxy-γ-aminobutyric acid compound, characterized in that: The following steps are involved: Dispersing nitroaromatic hydrocarbons, acrylic acid, a carbon source, a hydrogen source, a catalyst and a basic additive in an organic solvent, placing the mixture in a protective atmosphere for reaction, and obtaining an α-hydroxy-γ-aminobutyric acid compound; α-Hydroxy-γ-aminobutyric acid compounds, whose structure is The nitroaromatic hydrocarbon is Where R 1 is one or two of hydrogen, methyl, ethyl, methoxy, halogen, carboxyl, trifluoromethyl, cyano, and aldehyde; The acrylic acid is The carbon source is at least one of formaldehyde and paraformaldehyde; the hydrogen source is at least one of formic acid, sodium formate, and phenylsilane; The catalyst is a cobalt-nitrogen co-doped porous carbon material; the cobalt-nitrogen co-doped porous carbon material is prepared by the following method: dispersing cobalt acetate, 5,6-diamino-1,10-phenanthroline and carbon powder in an organic solvent, separating the solid and pyrolyzing it at 700° C. to 900° C. for 2 h to 3 h to obtain the cobalt-nitrogen co-doped porous carbon material; The alkaline additive is at least one of pyridine, 1,8-diazabicycloundec-7-ene, and triethylamine.

2. The method for preparing the α-hydroxy-γ-aminobutyric acid compound according to claim 1, characterized in that: The nitroaromatic hydrocarbon is one of nitrobenzene, p-ethylnitrobenzene, p-fluoronitrobenzene, m-nitrobenzenenitrile, m-nitrobenzaldehyde, and 2-bromo-4-nitroanisole; The carbon source is paraformaldehyde; The hydrogen source is formic acid.

3. The method for preparing the α-hydroxy-γ-aminobutyric acid compound according to claim 1, characterized in that: In the preparation of cobalt-nitrogen co-doped porous carbon material, the mass ratio of cobalt acetate, 5,6-diamino-1,10-phenanthroline, and carbon powder is 0.1-0.5:0.3-0.6:1; In the preparation of cobalt-nitrogen co-doped porous carbon material, the organic solvent is ethanol.

4. The method for preparing the α-hydroxy-γ-aminobutyric acid compound according to claim 1, characterized in that: The molar ratio of the nitroaromatic hydrocarbon, acrylic acid, carbon source, and hydrogen source is (1.1-1.6):1:(1.3-1.6):(6-7); The molar ratio of cobalt to acrylic acid in the catalyst is 0.04 to 0.06:1; The molar ratio of the alkaline additive to the nitroaromatic hydrocarbon is 0.2 to 0.6:

1.

5. The method for preparing the α-hydroxy-γ-aminobutyric acid compound according to claim 4, characterized in that: The molar ratio of the nitroaromatic hydrocarbon, acrylic acid, carbon source, and hydrogen source is 1.3-1.6:1:1.3-1.6:6-7; The alkaline additive is pyridine.

6. The method for preparing the α-hydroxy-γ-aminobutyric acid compound according to claim 1, characterized in that: In the preparation of α-hydroxy-γ-aminobutyric acid compounds, the organic solvent is at least one of methanol, ethanol, toluene, tetrahydrofuran, and acetonitrile; The protective atmosphere is a nitrogen atmosphere or an argon atmosphere; The reaction is carried out at 80°C to 100°C; The reaction time is 16h to 20h; After the reaction was completed, the reaction product was purified by column chromatography.

7. The method for preparing the α-hydroxy-γ-aminobutyric acid compound according to claim 6, characterized in that: The organic solvent is tetrahydrofuran; The eluent used in the column chromatography purification is prepared by mixing petroleum ether, ethyl acetate and methanol in a volume ratio of 1-10:2-4:1.

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