Rapid synthesis method of beta-amino acid derivative

Abstract

The invention belongs to the technical field of organic synthesis, and discloses a rapid synthesis method of a beta-amino acid derivative. The method comprises the following steps: by taking an organic solvent as a reaction medium, reacting 3-hexenoic acid with a dioxazolone compound under the action of pinacolborane, a catalyst, silver salt and an alkaline compound to obtain the beta-amino acid derivative, the structure of the beta-amino acid derivative is as shown in formula I, and R is aryl, furyl, aryl-substituted alkenyl or 3, 4-methylenedioxy phenyl; the catalyst is a dichloro (pentamethyl cyclopentadienyl) rhodium (III) dimer; the organic solvent is a fluorine-containing alcohol solvent. The method has the advantages of mild reaction conditions, no need of nitrogen protection, one-step synthesis of the beta-amino acid derivative, and low energy consumption; the method provided by the invention has high chemical selectivity and high product yield. # imgabs0 #

Description

Technical Field

[0001] The invention belongs to the technical field of organic synthesis, and specifically relates to a rapid synthesis method of beta-amino acid derivatives. Background Art

[0002] β-amino acids are an important class of synthetic building blocks, and a large number of drugs containing natural or unnatural β-amino acid residues have been widely used in the pharmaceutical industry. First, widely used antibiotics contain a large number of β-amino acid residues. For example, β-lactam antibiotics can be prepared by β-amino acid condensation; antibiotics PyloricidinA and MoiramideA contain (S)-β-phenylalanine residues; cispentacin, which has good antibacterial effects isolated from Bacillus cereus, is also a cyclic β-amino acid. Secondly, some drugs or drug intermediates also contain β-amino acid residues, such as acute coronary heart disease drug omixaban, diabetes drug sitagliptin, anti-AIDS drug maraviroc, etc. Later, scientists discovered that β-amino acids also have great potential in the synthesis of peptide drug molecules. Compared with peptides synthesized using α-amino acids, peptide molecules synthesized using β-amino acids also have good biological activity, and have good tolerance to protease hydrolysis and a longer half-life. Therefore, the use of β-amino acids as peptide drug skeletons has become a hot topic of research. β-Amino acid molecules have a wide range of applications as drugs and agricultural chemicals, and are prominent representatives in medicinal chemistry (Peptides Containing β-Amino Acid Patterns: Challenges and Successes in Medicinal Chemistry. J. Med. Chem. 2014, 57, 9718-9739.). For example, Lanthipeptide A (Angiotensin-(1-7) with Thioether Bridge: An Angiotensin-Converting Enzyme-Resistant, Potent Angiotensin-(1-7) Analog. J. Pharmacol. Exp. Ther. 2009, 328, 849-854.) is currently being used as a specific drug for the treatment of renal vasodilation. β-Amino acids are also incorporated into proteins through genetic code expansion (In Vivo Biosynthesis of aβ-Amino Acid-Containing Protein. J. Am. Chem. Soc. 2016, 138, 5194-5197.), which has great potential utility in biotechnology.

[0003] As a versatile nitrogen source, dioxazolones are combined with transition metal catalyst systems to promote decarboxylation reactions to obtain key metal-acyl nitrogen amide intermediates. In addition to their high robustness and easy access from abundant carboxylic acids, the unique reactivity of transient intermediates in transamination has led to fruitful results in mild and efficient CH amidation reactions. In addition to various conventional chemical processes, the synthesis of β-amino acids also includes enantioselective hydrogenation of β-enyl amino acids, asymmetric Mannich reaction, and reductive amination and enzyme catalysis of β-keto acids and their derivatives. However, there is no hydroamination reaction involving carboxylic acids in ene carboxylic acids as directing groups to synthesize β-amino acids. This limits the synthesis of such compounds and their applications in biomedicine, synthesis of natural products, and other fields. Therefore, exploring synthetic strategies with cheap and readily available raw materials, mild reaction conditions, high selectivity, and environmental friendliness remains an extremely attractive research topic. Summary of the invention

[0004] The purpose of the present invention is to provide a rapid synthesis method of β-amino acid derivatives to solve the many defects of existing β-amino acid synthesis. The method of the present invention has mild reaction conditions, cheap and readily available raw materials, and can rapidly synthesize β-amino acid derivatives in one step with high specificity.

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

[0006] A rapid synthesis method for a beta-amino acid derivative comprises the following steps: using an organic solvent as a reaction medium, reacting 3-hexenoic acid with a dioxazolone compound under the action of pinacol borane, a catalyst, a silver salt and an alkaline compound to obtain the beta-amino acid derivative.

[0007] The structure of 3-hexenoic acid is

[0008]

[0009] The structure of oxazolone compounds is

[0010]

[0011] The structure of β-amino acid derivatives is

[0012] Formula I:

[0013] In the above structure, R is aryl, furyl, aryl-substituted alkenyl, or 3,4-methylenedioxyphenyl;

[0014] The aryl group is phenyl or substituted phenyl; the substituent in the substituted phenyl group is trifluoromethyl, methoxy or ethoxy; specifically, p-trifluoromethylphenyl, m-methoxyphenyl, p-methoxyphenyl, p-ethoxyphenyl or m-ethoxyphenyl;

[0015] The aryl group in the aryl-substituted alkenyl group is a phenyl group; preferably, the aryl-substituted alkenyl group is a styryl group.

[0016] The dioxazolone compound is specifically one of the following compounds:

[0017]

[0018] The catalyst is dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer.

[0019] The solvent is a fluorine-containing alcohol solvent, specifically one or more of hexafluoroisopropanol and high-fluorinated tert-butyl alcohol.

[0020] The reaction temperature is 30-80° C., preferably 40-80° C. The reaction time is 12-24 hours.

[0021] The silver salt is one or more of silver carbonate, silver nitrate, silver sulfate, and silver tetrafluoroborate, preferably one or more of silver carbonate, silver nitrate, and silver sulfate.

[0022] The alkaline compound is one or more of cesium acetate, cesium pivalate, cesium fluoride, and cesium hydroxide monohydrate, preferably one or more of cesium acetate, cesium pivalate, and cesium hydroxide monohydrate.

[0023] The molar ratio of the 3-hexenoic acid to the dioxazolone compound is 1:(1-2); the molar ratio of the 3-hexenoic acid to the pinacol borane is 1:(1-2);

[0024] The amount of the catalyst used is 0.5% to 1.5% of the molar amount of 3-hexenoic acid;

[0025] The amount of the alkaline compound is 0.5 to 1.5 times the molar amount of 3-hexenoic acid;

[0026] The amount of the silver salt used is 20% to 35% of the molar amount of 3-hexenoic acid.

[0027] After the reaction, the mixture was dried by rotation and separated by polar column chromatography. The solvent was petroleum ether / ethyl acetate / formic acid in a volume ratio of 50 / (10-30) / 1.

[0028] Reaction equation of the present invention:

[0029]

[0030] Compared with the prior art, the present invention has the following beneficial effects:

[0031] 1) The reaction conditions are mild and no nitrogen protection is required. The β-amino acid is synthesized in one step under relatively low temperature conditions, and the low energy consumption is beneficial to environmental protection and industrial-scale production.

[0032] 2) The reaction is highly chemically selective and has a high product yield.

[0033] 3) The reaction has a wide range of substrates and strong functional group compatibility. BRIEF DESCRIPTION OF THE DRAWINGS

[0034] Figure 1 The hydrogen spectrum of compound 3a ( 1 H NMR: 400 MHz, DMSO-d6)

[0035] Figure 2 The carbon spectrum of compound 3a is ( 13 C NMR: 101 MHz, DMSO-d6)

[0036] Figure 3 The hydrogen spectrum of compound 3b ( 1 H NMR: 500 MHz, DMSO-d6)

[0037] Figure 4 The carbon spectrum of compound 3b is ( 13 C NMR: 126 MHz, DMSO-d6)

[0038] Figure 5 The hydrogen spectrum of compound 3c ( 1 H NMR: 500 MHz, DMSO-d6)

[0039] Figure 6 The carbon spectrum of compound 3c ( 13 C NMR: 126 MHz, DMSO-d6)

[0040] Figure 7 is the 3d hydrogen spectrum of the compound ( 1 H NMR: 500 MHz, DMSO-d6)

[0041] Figure 8 is the 3d carbon spectrum of the compound ( 13 C NMR: 126 MHz, DMSO-d6)

[0042] Fig. 9 The hydrogen spectrum of compound 3e is ( 1 H NMR: 500 MHz, DMSO-d6)

[0043] Fig.10 The carbon spectrum of compound 3e is ( 13 C NMR: 126 MHz, DMSO-d6)

[0044] Fig.11 The hydrogen spectrum of compound 3f (1 H NMR: 500 MHz, DMSO-d6)

[0045] Fig.12 The 3f carbon spectrum of the compound ( 13 C NMR: 126 MHz, DMSO-d6)

[0046] Fig.13 The hydrogen spectrum of compound 3g is ( 1 H NMR: 500 MHz, DMSO-d6)

[0047] Fig.14 The carbon spectrum of compound 3g is ( 13 C NMR: 126 MHz, DMSO-d6)

[0048] Fig.15 This is the X-ray crystal structure of compound 3a. DETAILED DESCRIPTION

[0049] The present invention is further described in detail below in conjunction with specific examples, but the embodiments of the present invention are not limited thereto.

[0050] Example 1 Synthesis of β-Benzoylaminocaproic acid 3a

[0051] At room temperature, 3-hexenoic acid 1a (0.01 mol, 1.14 g), 3-phenyl-1,4,2-dioxazol-5-one 2a (1.96 g) and pinacol borane (2.56 g) were added as initial raw materials into a container, and then catalyst dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer (0.06 g), silver sulfate (0.94 g) and cesium acetate (1.92 g) were added, and finally 100 ml of hexafluoroisopropanol was added, the container was placed in air, moved to a 40° C. oil bath and stirred, and reacted for 12 hours; the reaction was detected by spot plate, and when the raw material 1a was completely converted, the mixture was cooled to room temperature, spin-dried to obtain a crude product, and then separated by polar column chromatography (petroleum ether / ethyl acetate / formic acid: 50 / 10 / 1 to 50 / 30 / 1) to obtain a white solid compound 3a (2.30 g) with a yield of 98%.

[0052]

[0053] Product 3a structural formula:

[0054]

[0055] NMR spectrum data of product 3a: 1H NMR(400MHz,DMSO-d6)δ12.17(s,1H),8.21(d,J=8.6Hz,1H),7.86-7.80(m,2H),7.55-7.43(m,3H),4.41 -4.19(m,1H),2.48(dd,J=17.6,7.0Hz,2H),1.61-1.44(m,2H),1.41-1.21(m,2H),0.88(t,J=7.3Hz,3H). 13 C NMR (101 MHz, DMSO-d6) δ 173.09, 166.22, 135.24, 131.47, 128.63, 127.67, 46.60, 36.73, 19.30, 14.26. Hydrogen and carbon spectra are shown in Figure 1 and 2 shown.

[0056] Fig.15 This is the X-ray crystal structure of compound 3a. Fig.15 It can be seen that the product obtained is a β-amino acid. Not only does NMR confirm the structure, but the X-ray crystal structure diagram also confirms that the product structure is a β-amino acid.

[0057] Example 2 Synthesis of β-p-Nitrobenzoylaminocaproic acid 3b

[0058] At room temperature, 3-hexenoic acid 1a (0.01mol, 1.14g), 3-trifluoromethylphenyl-1,4,2-dioxazol-5-one 2b (2.77g) and pinacol borane (2.56g) were added to the reaction vessel as the initial raw materials, and then the catalyst dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer (0.06g), silver sulfate (0.94g) and cesium acetate (1.92g) were added, and finally 100ml of hexafluoroisopropanol was added, and the reaction vessel was placed in the air. Move to a 40°C oil bath pot and stir, react for 12 hours, and detect the reaction status with a plate. When the raw material 1a is completely converted, the mixture is cooled to room temperature, spin-dried to obtain a crude product, and then separated by polar column chromatography (petroleum ether / ethyl acetate / formic acid: 50 / 10 / 1 to 50 / 30 / 1), and a white solid compound 3b (2.67g) is obtained, and the yield is 88%.

[0059]

[0060] Product 3b structural formula:

[0061]

[0062] NMR spectrum data of product 3b: 1H NMR (500MHz, DMSO-d6) δ12.18(s,1H),8.47(d,J=8.5Hz,1H),8.02(d,J=8.1Hz,2H),7.84(d,J=8.2Hz,2H),4 .38-4.29(m,1H),2.46(dd,J=15.2,6.5Hz,2H),1.61-1.46(m,2H),1.40-1.23(m,2H),0.88(t,J=7.3Hz,3H). 13 C NMR (126 MHz, DMSO-d6) δ 172.99, 165.08, 138.97, 131.61, 131.35, 128.57, 125.73, 125.70, 125.67, 125.64, 123.34, 46.85, 36.64, 19.26, 14.19. Hydrogen and carbon spectra are shown in Figure 3 and 4 shown.

[0063] Example 3 Synthesis of β-(3,4-methylenedioxyphenyl)formamidohexanoic acid 3c

[0064] At room temperature, 3-hexenoic acid 1a (0.01 mol, 1.14 g), 3-(3,4-methylenedioxyphenyl)-1,4,2-dioxazol-5-one 2c (2.49 g) and pinacol borane (2.56 g) were added as initial raw materials to a reaction vessel, and then the catalyst dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.06 g), silver sulfate (0.94 g) and cesium acetate (1.92 g) were added, and finally 100 ml of hexafluoroisopropanol was added, and the reaction vessel was placed in the air. The mixture was transferred to an oil bath at 40°C with stirring and reacted for 12 hours. The reaction status was monitored by spot plate. When the raw material 1a was completely converted, the mixture was cooled to room temperature and dried to obtain a crude product. The crude product was then separated by polar column chromatography (petroleum ether / ethyl acetate / formic acid: 50 / 10 / 1 to 50 / 30 / 1) to obtain white solid compound 3c (2.35 g) with a yield of 84%.

[0065]

[0066] Product 3c structural formula:

[0067]

[0068] NMR spectrum data of product 3c: 1H NMR(500MHz,DMSO-d6)δ12.12(s,1H),8.04(d,J=8.5Hz,1H),7.51-7.24(m,2H),6.98(d,J=8.1Hz,1H),6.09 (s,2H),4.40-4.16(m,1H),2.50-2.37(m,2H),1.58-1.41(m,2H),1.39-1.20(m,2H),0.87(t,J=7.3Hz,3H). 13 C NMR (126 MHz, DMSO-d6) δ 173.10, 165.26, 149.97, 147.69, 129.18, 122.59, 108.20, 107.79, 102.06, 46.64, 36.72, 19.28, 14.26. Hydrogen and carbon spectra are shown in Figure 5 and 6 shown.

[0069] Example 4 Synthesis of β-m-methoxybenzamidohexanoic acid 3d

[0070] At room temperature, 3-hexenoic acid 1a (0.01mol, 1.14g), 3-m-methoxyphenyl-1,4,2-dioxazol-5-one 2d (3.18g) and pinacol borane (2.56g) were added to the reaction vessel as the initial raw materials, and then the catalyst dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer (0.06g), silver sulfate (0.94g) and cesium acetate (1.92g) were added, and finally 100ml of hexafluoroisopropanol was added, and the reaction vessel was placed in the air. Move to a 40°C oil bath pot and stir, react for 12 hours, and detect the reaction status with a plate. When the raw material 1a is completely converted, the mixture is cooled to room temperature, spin-dried to obtain a crude product, and then separated by polar column chromatography (petroleum ether / ethyl acetate / formic acid: 50 / 10 / 1 to 50 / 30 / 1), and a white solid compound 3d (2.07g) is obtained, and the yield is 78%.

[0071]

[0072] Product 3d structure:

[0073]

[0074] Product 3D NMR spectrum data: 1H NMR(500MHz,DMSO-d6)δ12.26(s,1H),8.24(d,J=8.5Hz,1H),7.51–7.35(m,3H),7.16–7.06(m,1H),4.46– 4.23(m,1H),3.84(s,3H),2.54–2.44(m,2H),1.63–1.48(m,2H),1.43–1.24(m,2H),0.91(t,J=7.3Hz,3H). 13 C NMR (126 MHz, DMSO-d6) δ 173.10, 165.92, 159.58, 136.65, 129.77, 119.88, 117.19, 113.01, 55.70, 46.64, 36.71, 19.30, 14.26. Hydrogen and carbon spectra are shown in Figure 7 and 8 shown.

[0075] Example 5 Synthesis of β-furancarboxamidohexanoic acid 3e

[0076] At room temperature, 3-hexenoic acid 1a (0.01 mol, 1.14 g), 3-furyl-1,4,2-dioxazol-5-one 2e (1.84 g) and pinacol borane (2.56 g) were added as initial raw materials to a reaction vessel, and then catalyst dichloro(pentamethylcyclopentadienyl)rhodium (III) dimer (0.06 g), silver sulfate (0.94 g) and cesium acetate (1.92 g) were added, and finally 100 ml of hexafluoroisopropanol was added. The reaction vessel was placed in air, moved to a 40° C. oil bath and stirred, and reacted for 12 hours. The reaction was detected by spot plate. When the raw material 1a was completely converted, the mixture was cooled to room temperature, spin-dried to obtain a crude product, and then separated by polar column chromatography (petroleum ether / ethyl acetate / formic acid: 50 / 10 / 1 to 50 / 30 / 1) to obtain a white solid compound 3e (1.53 g) with a yield of 68%.

[0077]

[0078] Product 3e structural formula:

[0079]

[0080] NMR spectrum data of product 3e: 1H NMR (500MHz, DMSO-d6) δ12.17(s,1H),8.12(d,J=8.9Hz,1H),7.81(s,1H),7.06(d,J=3.4Hz,1H),6.60(s ,1H),4.38–4.05(m,1H),2.48–2.37(m,2H),1.55–1.40(m,2H),1.32–1.21(m,3H),0.85(t,J=7.4Hz,3H). 13 C NMR (126MHz, DMSO-d6)δ173.12,157.60,148.46,145.21,113.67,112.27,45.83,36.69,19.27,14.20. Hydrogen and carbon spectra are shown in Fig. 9 and 10 shown.

[0081] Example 6 Synthesis of β-(2-phenylvinyl)formylaminocaproic acid 3f

[0082] At room temperature, 3-hexenoic acid 1a (0.01 mol, 1.14 g), 3-(2-phenylvinyl)-1,4,2-dioxazol-5-one 2f (2.27 g) and pinacol borane (2.56 g) were added as initial raw materials to a reaction vessel, and then catalyst dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.06 g), silver sulfate (0.94 g) and cesium acetate (1.92 g) were added, and finally 100 ml of hexafluoroisopropanol was added. The reaction vessel was placed in air, moved to a 40° C. oil bath and stirred, and reacted for 12 hours. The reaction was detected by spot plate. When the raw material 1a was completely converted, the mixture was cooled to room temperature, spin-dried to obtain a crude product, and then separated by polar column chromatography (petroleum ether / ethyl acetate / formic acid: 50 / 10 / 1 to 50 / 30 / 1) to obtain a white solid compound 3f (2.09 g) with a yield of 80%.

[0083]

[0084] Product 3f structural formula:

[0085]

[0086] Product 3f NMR spectrum data: 1H NMR (500MHz, DMSO-d6) δ12.17(s,1H),7.98(d,J=8.5Hz,1H),7.56(d,J=7.0Hz,2H),7.44–7.38(m,3H),6.63(d,J=15.8Hz, 1H),4.40–4.01(m,1H),2.52–2.49(m,1H),2.46–2.35(m,2H),1.53–1.39(m,2H),1.36–1.21(m,2H),0.87(t,J=7.3Hz,3H). 13 C NMR (126 MHz, DMSO-d6) δ 172.96, 164.79, 139.02, 135.42, 129.83, 129.39, 127.92, 122.86, 46.12, 40.10, 36.67, 19.15, 14.24. Hydrogen and carbon spectra are shown in Fig.11 and 12 shown.

[0087] Comparative Example 1 Synthesis of 3 g of γ-p-fluorophenyl-β-benzamide butyric acid

[0088] At room temperature, add γ-p-fluorophenyl-3-butenoic acid 1b (0.01mol, 1.80g), 3-phenyl-1,4,2-dioxazol-5-one 2a (1.96g) and pinacol borane (2.56g) as initial raw materials to the reaction vessel, then add the catalyst dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer (0.06g), silver sulfate (0.94g) and cesium acetate (1.92g), and finally add 100ml hexafluoroisopropanol, and place the reaction vessel in the air. Move to a 40°C oil bath and stir, and react for 12 hours. Spot plate to detect the reaction. When the raw material 1a is completely converted, the mixture is cooled to room temperature, spin-dried to obtain a crude product, and then separated by polar column chromatography (petroleum ether / ethyl acetate / formic acid: 50 / 10 / 1 to 50 / 30 / 1), and a white solid compound 3g 0.48g is obtained, with a yield of 16%. The chemical selectivity is at the β position, but because the olefin is connected to a p-fluorophenyl group, the steric hindrance is increased, resulting in poor reaction efficiency and low yield.

[0089]

[0090] Product 3g structural formula:

[0091]

[0092] NMR spectrum data of product 3g: 1H NMR (500MHz, DMSO-d6) δ12.24(s,1H),8.35(d,J=8.4Hz,1H),7.80–7.72(m,2H),7.51(t,J=7.3Hz,1H),7.44(t,J= 7.5Hz,2H),7.28–7.23(m,2H),7.09(t,J=8.7Hz,2H),4.52–4.43(m,1H),2.86(d,J=6.9Hz,2H),2.58–2.51(m,2H). 13 C NMR (126 MHz, DMSO-d6) δ 172.92, 166.18, 162.28, 160.36, 135.35, 135.32, 135.09, 131.53, 131.42, 131.35, 128.65, 127.61, 115.40, 115.24, 48.64, 39.30, 39.26. Hydrogen and carbon spectra are shown in Fig.13 and 14 shown.

[0093] Comparative Example 2 Synthesis of β-acetylaminocaproic acid formamidocaproic acid 3h

[0094] At room temperature, 3-hexenoic acid 1a (0.01 mol, 1.14 g), 3-methyl-1,4,2-dioxazol-5-one 2h (1.21 g) and pinacol borane (2.56 g) were added as initial raw materials to the reaction vessel, and then the catalyst dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.06 g), silver sulfate (0.94 g) and cesium acetate (1.92 g) were added, and finally 100 ml of hexafluoroisopropanol was added. The reaction vessel was placed in air, moved to a 40°C oil bath and stirred. The reaction was reacted for 12 hours. The reaction was detected by spot plate. The spot plate found that no product was produced, the raw materials remained, and the alkyl oxazolone was incompatible in the reaction.

[0095]

[0096] Comparative Example 3 Synthesis of β-cyclopentanecarboxamidohexanoic acid carboxamidohexanoic acid 3i

[0097] At room temperature, 3-hexenoic acid 1a (0.01 mol, 1.14 g), 3-cyclopentyl-1,4,2-dioxazol-5-one 2i (1.86 g) and pinacol borane (2.56 g) were added to the reaction vessel as initial raw materials, and then the catalyst dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer (0.06 g), silver sulfate (0.94 g) and cesium acetate (1.92 g) were added, and finally 100 ml of hexafluoroisopropanol was added, and the reaction vessel was placed in the air, moved to a 40°C oil bath pot and stirred, reacted for 12 hours, and the reaction was detected by spot plate. Spot plate found that no product was produced, raw materials remained, and alkyl oxazolone was incompatible in this reaction.

[0098] Comparative Example 4 Synthesis of β-Benzoylaminocaproic acid 3a

[0099] At room temperature, 3-hexenoic acid 1a (0.01 mol, 1.14 g), 3-phenyl-1,4,2-dioxazol-5-one 2i (1.96 g) and pinacol borane (2.56 g) were added to the reaction vessel as initial raw materials, and then the catalyst nickel iodide (0.03 g), silver sulfate (0.94 g) and cesium acetate (1.92 g) were added, and finally 100 ml of hexafluoroisopropanol was added, and the reaction vessel was placed in the air, moved to a 40°C oil bath pot and stirred, reacted for 12 hours, and the reaction was detected by spot plate. Spot plate found that no product was produced, raw materials were left, and the catalyst nickel iodide could not catalyze the reaction.

[0100]

[0101] Comparative Example 5 Synthesis of β-Benzoylaminocaproic acid 3a

[0102] At room temperature, 3-hexenoic acid 1a (0.01 mol, 1.14 g), 3-phenyl-1,4,2-dioxazol-5-one 2a (1.96 g) and pinacol borane (2.56 g) were added to the reaction vessel as initial raw materials, and then the catalyst dichloro (pentamethylcyclopentadienyl) iridium (III) dimer (0.08 g), silver sulfate (0.94 g) and cesium acetate (1.92 g) were added, and finally 100 ml of hexafluoroisopropanol was added, and the reaction vessel was placed in the air, moved to a 40°C oil bath pot and stirred, reacted for 12 hours, and the reaction was detected by spot plate. Spot plate found that no product was produced, raw materials were left, and the catalyst dichloro (pentamethylcyclopentadienyl) iridium (III) dimer could not catalyze the reaction.

[0103]

[0104] Comparative Example 6 Synthesis of β-Benzoylaminocaproic acid 3a

[0105] At room temperature, 3-hexenoic acid 1a (0.01 mol, 1.14 g), 3-phenyl-1,4,2-dioxazol-5-one 2a (1.96 g) and pinacol borane (2.56 g) were added as initial raw materials to a reaction vessel, and then catalyst dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer (0.06 g), silver acetate (0.50 g) and cesium acetate (1.92 g) were added, and finally 100 ml of hexafluoroisopropanol was added. The reaction vessel was placed in air, moved to a 40°C oil bath and stirred, reacted for 12 hours, and the reaction was detected by spot plate. The mixture was cooled to room temperature, spin-dried to obtain a crude product, and then separated by polar column chromatography (petroleum ether / ethyl acetate / formic acid: 50 / 10 / 1 to 50 / 30 / 1) to obtain white solid compound 3a (1.13 g) with a yield of 48%.

[0106]

[0107] Product 3a structural formula:

[0108]

[0109] Comparative Example 7 Synthesis of β-Benzoylaminocaproic acid 3a

[0110] At room temperature, 3-hexenoic acid 1a (0.01 mol, 1.14 g), 3-phenyl-1,4,2-dioxazol-5-one 2a (1.96 g) and pinacol borane (2.56 g) were added to the reaction vessel as initial raw materials, and then the catalyst dichloro (pentamethylcyclopentadienyl) rhodium (III) dimer (0.06 g), silver sulfate (0.50 g) and sodium acetate (0.82 g) were added, and finally 100 ml of hexafluoroisopropanol was added, and the reaction vessel was placed in the air, moved to a 40°C oil bath pot and stirred, reacted for 12 hours, and the reaction was detected by spot plate. Spot plate found that no product was produced, raw materials were left, and sodium carbonate was not effective in this reaction.

[0111]

[0112] The catalyst, silver salt, base and solvent were adjusted, and the other steps were the same as in Example 1. The yields of the obtained products are shown in Table 1.

[0113] Table 1 Product yields under different conditions

[0114]

[0115]

[0116] It is easy for those skilled in the art to understand that the specific embodiments described herein are only used to explain the present invention and are not intended to limit the present invention. Any modification, equivalent replacement or improvement made within the spirit and principle of the present invention shall be included in the protection scope of the present invention.

Claims

1. A rapid synthesis method of β-amino acid derivatives, characterized in that: The following steps are involved: Using an organic solvent as a reaction medium, 3-hexenoic acid reacts with a dioxazolone compound under the action of pinacol borane, a catalyst, a silver salt and an alkaline compound to obtain a β-amino acid derivative; The structure of dioxazolone compounds is The structure of β-amino acid derivatives is In the above structure, R is aryl, furyl, aryl-substituted alkenyl, or 3,4-methylenedioxyphenyl; The catalyst is dichloro(pentamethylcyclopentadienyl)rhodium(III) dimer; The organic solvent is a fluorine-containing alcohol solvent; The alkaline compound is one or more of cesium acetate, cesium pivalate, cesium fluoride, and cesium hydroxide monohydrate.

2. The rapid synthesis method of β-amino acid derivatives according to claim 1, characterized in that: The aryl group in R is phenyl or substituted phenyl; the substituent in the substituted phenyl is trifluoromethyl, methoxy or ethoxy; The aryl group in the aryl-substituted alkenyl group is phenyl.

3. The rapid synthesis method of β-amino acid derivatives according to claim 2, characterized in that: The substituted phenyl group is p-trifluoromethylphenyl, m-methoxyphenyl, p-methoxyphenyl, p-ethoxyphenyl, m-ethoxyphenyl; The aryl-substituted alkenyl group is a styryl group.

4. The rapid synthesis method of β-amino acid derivatives according to claim 3, characterized in that: The dioxazolone compound is specifically one of the following compounds:

5. The rapid synthesis method of β-amino acid derivatives according to claim 1, characterized in that: The organic solvent is one or more of hexafluoroisopropanol and high-fluorinated tert-butyl alcohol; The reaction temperature is 30-80°C; The silver salt is one or more of silver carbonate, silver nitrate, silver sulfate and silver tetrafluoroborate; The alkaline compound is one or more of cesium acetate, cesium pivalate, and cesium hydroxide monohydrate.

6. The method for rapid synthesis of β-amino acid derivatives according to claim 5, characterized in that: The silver salt is one or more of silver carbonate, silver nitrate and silver sulfate.

7. The method for rapid synthesis of β-amino acid derivatives according to claim 1, characterized in that: The amount of the catalyst used is 0.5% to 1.5% of the molar amount of 3-hexenoic acid; The amount of the alkaline compound is 0.5 to 1.5 times the molar amount of 3-hexenoic acid; The amount of the silver salt used is 20% to 35% of the molar amount of 3-hexenoic acid.

8. The method for rapid synthesis of β-amino acid derivatives according to claim 1, characterized in that: The molar ratio of the 3-hexenoic acid to the dioxazolone compound is 1:(1-2); the molar ratio of the 3-hexenoic acid to the pinacol borane is 1:(1-2.5).

9. The method for rapid synthesis of β-amino acid derivatives according to claim 1, characterized in that: The reaction time is 12-24h; After the reaction is completed, the mixture is dried by rotation and separated by polar column chromatography. The solvent used in the column chromatography separation is petroleum ether / ethyl acetate / formic acid, and the volume ratio of petroleum ether:ethyl acetate:formic acid is 50:(10-30):

1.

10. Use of a β-amino acid derivative obtained by the method according to any one of claims 1 to 9 in the preparation of crude drugs and peptides or proteins.

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