Synthesis method of amino acid compound

Abstract

The invention discloses a synthesis method of an amino acid compound, and belongs to the technical field of organic synthesis. The synthesis method comprises the following steps: mixing benzylamine and derivatives thereof, a photocatalyst and alkali, and then adding an HAT reagent and a solvent in a CO2 atmosphere to obtain a reaction solution; stirring the reaction liquid for reaction under the conditions of illumination and room temperature, and acidifying, separating and purifying the reaction product to obtain the amino acid compound. Or mixing amide and derivatives thereof, a photocatalyst and alkali, and then adding a solvent in a CO2 atmosphere to obtain a reaction solution; stirring and reacting the reaction liquid under illumination and heating conditions, and acidifying, separating and purifying the reaction product to obtain the amino acid compound. The preparation method disclosed by the invention shows excellent reactivity to benzylamine and derivatives thereof and amide and derivative substrates thereof, and has the characteristics of convenience in operation, cheap and easily available raw materials, mild reaction conditions, wide substrate universality and high product yield.

Description

Technical Field

[0001] This invention relates to the field of organic synthesis technology, and more specifically to a method for synthesizing amino acid compounds. Background Technology

[0002] α -amino acids ( α -AAs are core structural units that make up peptide chains, proteins, and many natural products and drugs in living organisms. Developing efficient and green synthetic methods for them is of great significance. Currently, synthetic strategies utilizing carbon dioxide (CO2) as a Cl source are widely developed, mainly divided into two categories: one is the traditional carboxylation reaction based on substrates such as enamines, acetylacetonates, and imines; the other is the more advanced amine compound synthesis. α The direct C(sp³)-H bond carboxylation strategy, in which visible light photocatalysis, with its mild conditions and unique reactivity, has become a popular approach for achieving carboxylation of amine compounds. α The CH bond is activated and subsequently combines with CO2 to generate... α -amino acids ( α -AAs) are effective tools.

[0003] However, all of the above methods have significant limitations. Traditional methods heavily rely on stoichiometric organometallic reagents, high CO2 pressures, or cumbersome prefunctionalization steps, resulting in poor atom and step economy, thus reducing the economic benefits of large-scale applications. While emerging photocatalytic carboxylation methods offer significant advantages, their successful applications are currently limited to tertiary amines or amide substrates with specific structures. For widely available primary amines with higher carboxylation value (such as benzylamine), due to their high oxidation potential, strong nucleophilicity, and tendency to undergo excessive oxidation to form imines or nitriles, existing photocatalytic strategies have not yet been able to achieve their direct carboxylation. α -CH carboxylation has become a key scientific challenge that urgently needs to be overcome in this field. Summary of the Invention

[0004] To address the aforementioned shortcomings of existing technologies, the present invention aims to provide a method for synthesizing amino acid compounds.

[0005] The technical solution of this invention to solve the above-mentioned technical problems is as follows: A method for synthesizing amino acid compounds is provided, comprising the following steps: Benzylamine and its derivatives, a photocatalyst, and a base were mixed, and then HAT reagent and a solvent were added under a CO2 atmosphere to obtain a reaction solution. The reaction solution was stirred under light and room temperature conditions, and then the reaction product was acidified and purified to obtain an amino acid compound. Alternatively, amides and their derivatives, photocatalysts, and bases can be mixed, and then a solvent can be added under a CO2 atmosphere to obtain a reaction solution. The reaction solution can be stirred under light and heating conditions, and then the reaction products can be acidified and purified to obtain amino acid compounds. The general structural formulas of the benzylamine and its derivatives are shown in Formula (I), and the general structural formulas of the amide and its derivatives are shown in Formula (II):

[0006] Among them, R 1 and R 2 Both are hydrogen and C 1-20 Alkyl, aryl and their substituted aryl, heteroaryl, ester, amide, cyano, halogen or carbonyl; R 3 For hydrogen, C 1-20 Alkyl or acyl; R 4 and R 5 Both are hydrogen and C 1-20 Alkyl, alkoxy, acyl, cyano, ester, halogen, aryl and their substituted aryl, heteroaryl or carbonyl; R 6 C 1-20 Alkyl, aryl, or alkoxy; The reaction formula is as follows: .

[0007] Furthermore, R 1 and R 2 All are phenyl groups substituted with hydrogen, biphenyl, trifluoromethyl (e.g., para-substituted, two meta-substituted), cyano-substituted (e.g., para-substituted), carboxymethyl-substituted (e.g., para-substituted), or carboxyethyl-substituted (e.g., para-substituted). , Trifluoromethoxy-substituted biphenyls (e.g., para-substituted), halogen-substituted biphenyls (e.g., ortho-substituted and / or meta-substituted), methyl, naphthyl, benzofuranyl, benzothiopheneyl; R 1 and R 2 The structures can be the same or different; R 3 It can be hydrogen, benzoyl (Bz), methyl, ethyl, or propyl (e.g., isopropyl).

[0008] Furthermore, the specific structures of benzylamine and its derivatives are as follows: .

[0009] Furthermore, R 4 and R 5All of these are phenyl groups substituted with hydrogen, phenyl, or methoxy (e.g., para-substituted, ortho-substituted), trifluoromethoxy-substituted (e.g., para-substituted), cyano-substituted (e.g., para-substituted), carboxymethyl-substituted (e.g., para-substituted), methanesulfonyl-substituted (e.g., para-substituted), halogen-substituted (e.g., meta-substituted), trifluoromethyl-substituted (e.g., meta-substituted), methyl-substituted (e.g., ortho-substituted), methyl, naphthyl, pyridyl, furanyl, thiophene, benzothiophene, etc. cyano ;R 4 and R 5 The structures can be the same or different; R 6 p-Methoxyphenyl (PMP), phenyl, .

[0010] Furthermore, the specific structures of amides and their derivatives are as follows: .

[0011] Further, the molar ratio of benzylamine and its derivatives, photocatalyst, base and HAT reagent is 1:0.0001~0.5:0.01~10:0.01~1; the molar ratio of the amide and its derivatives, photocatalyst and base is 1:0.0001~0.5:0.1~10.

[0012] Furthermore, the photocatalyst is an organic dye or an organometallic complex.

[0013] Furthermore, the photocatalyst is a DA-type photocatalyst or an Ir-type photocatalyst.

[0014] Further, the photocatalysts are 4CzIPN, 4DPAIPN, 3DPAFIPN, 3DPAFIPN-OMe, 3DPA2FBN, 5CzBN, 4CzPN, DPZ, 4CzPN-Ph, 4CzPN-Bu, 4CzTPN, 4CzTPN-Bu, Ir(dFCF3ppy)2(dtbbpy)PF6, fac -Ir(dF(ppy)3), fac At least one of -Ir(ppy)3 and Ir(ppy)2(dtbbpy)PF6.

[0015] Furthermore, the base is a tert-butoxide, carbonate, bicarbonate, fluoride, phosphate, hydrogen phosphate, carboxylate, or organic base.

[0016] Furthermore, tert-butoxide is a KO t Bu, NaO t Bu、LiO t Bu or Ca(O tBu)2; carbonates are Cs2CO3, K2CO3, Na2CO3 or Li2CO3; bicarbonates are CsHCO3, KHCO3 or NaHCO3; fluorides are CsF, KF, NaF or LiF; phosphates are K3PO4, Na3PO4 or Li3PO4; carboxylates are CsOAc, KOAc, NaOAc, CsOPiv, NaOPiv or KOPiv; organic bases are DBU, TBD, DABCO, TMG, DBN, TMEDA, Cy2NEt, Cy2NMe, PMP, NBu3, NMe3 or NET3.

[0017] Furthermore, the HAT reagent is an organosulfur compound.

[0018] Furthermore, the organosulfur compounds are C6H 13 SH, C8H 17 SH, C 10 S 21 SH, C 12 H 25 SH, C 16 H 33 SH p -MeOC6H4SH、 p -MeCO2C6H4SH、 p -FC6H4SH、 p - t BuC6H4SH、 p -NH2C6H4SH, CySH or (C6H 13 S)2.

[0019] Furthermore, the solvent is NMP, DMSO, DMF, DMAc, THF, DCM, MeOH, or MeCN; preferably, the solvent is DMAc.

[0020] Furthermore, the illumination is visible light with a wavelength of 300~700 nm.

[0021] Furthermore, the stirring reaction time at room temperature is 8–36 h.

[0022] Furthermore, the temperature of the stirring reaction under heating conditions is 20~60 ℃, and the stirring time is 4~24 h.

[0023] The present invention has the following beneficial effects: (1) This invention provides a method for synthesizing amino acid compounds by converting the -NH2 functional group of a primary amine into a carbamate in situ using CO2 in the reaction system. This conversion not only effectively suppresses the inherent strong nucleophilicity and excessive oxidation side reactions of primary amines, but more importantly, it may create favorable conditions for subsequent selective hydrogen atom transfer (HAT) processes, thereby generating the key amino acid compound under visible light catalysis. α -Amino radical intermediates, and ultimately achieve carboxylation with CO2, enabling the direct synthesis of free amino groups from inexpensive primary amines under mild conditions. α Amino acids offer a novel and promising solution. Specifically, under visible light catalysis, using benzylamine and its derivatives, as well as amides and their derivatives, as reaction substrates, and CO2 as the carboxyl source, along with a photocatalyst and a base, and selectively adding or omitting HAT reagents, amino acid compounds are prepared under mild conditions. This method is convenient to operate and uses inexpensive and readily available raw materials.

[0024] (2) The preparation method of the present invention exhibits excellent reactivity with benzylamine and its derivatives and amides and their derivative substrates, and focuses on realizing the α-C(sp) reaction of primary benzylamine compounds with visible light catalysis involving carbon dioxide. 3 The α-H bond carboxylation reaction was used to construct important α-amino acids ( α The -AAs molecule has the advantages of convenient operation, inexpensive and readily available raw materials, mild reaction conditions, broad substrate applicability and high product yield. Attached Figure Description

[0025] Figure 1 This is a diagram illustrating the reaction mechanism of the present invention. Detailed Implementation

[0026] The examples given below are for illustrative purposes only and are not intended to limit the scope of the invention. Unless otherwise specified, conditions in the examples are performed under standard conditions or as recommended by the manufacturer. Reagents or instruments whose manufacturers are not specified are all commercially available products.

[0027] The reaction mechanism of this invention is as follows: Figure 1 As shown, for benzylamine and its derivative substrates, taking 3DPAFIPN as a photocatalyst, 4-phenylbenzylamine as the benzylamine substrate, and CO2 as the carboxyl source as an example; the specific process is as follows: First, 3DPAFIPN is photoexcited to generate 3DPAFIPN. * In the presence of Cs₂CO₃, this species is reduced and quenched by in-situ generated thiolates via the SET process, producing sulfur radicals and 3DPAFIPN. •- Species. The generated sulfur radical seizes a radical from urethane intermediate A, which is formed in situ from an amino group and carbon dioxide. α- Hydrogen atoms generate benzyl radical species B and regenerate the thiol catalyst. Subsequently, intermediate B is reacted with 3DPAFIPN. •- Reduction generates a carbanion intermediate C and regenerates 3DPAFIPN. Subsequently, the carbanion attacks CO2 to generate a carboxylate intermediate D, which is then benzoylated and protonated to form the target compound. α - Amino acid derivatives.

[0028] For amide and its derivative substrates, taking 4DPAIPN as a photocatalyst, N-benzyl-4-methoxybenzamide as the amide substrate, and CO2 as the electrophilic reagent as an example; the specific process is as follows: First, 4DPAIPN is photoexcited to generate 4DPAIPN. * Species, in the presence of Cs2CO3, 4DPAIPN * The free radicals are quenched by amide via PCET or PT / ET pathways, generating nitrogen-centered free radical species E and 4DPAIPN. •- Subsequently, the radical intermediate E generates benzyl radical intermediate F via an intramolecular 1,2-HAT process, which is then reacted with 4DPAIPN. •- The reduction generates the corresponding carbanion G and regenerates 4DPAIPN. Subsequently, the carbanion attacks CO2 and, after protonation, generates the target. α - Amino acid derivatives.

[0029] The features and performance of the present invention will be further described in detail below with reference to embodiments.

[0030] Example 1: A synthesis based on CH bond carboxylation of benzylamine and its derivatives α The method for treating amino acid compounds is as follows: After drying a 10 mL Schlenk reaction tube equipped with a stirrer under vacuum, add 0.2 mmol of benzylamine and its derivatives (if the substrate is solid, add it at this stage; if the substrate is liquid, add it via syringe after adding the solvent) and the photocatalyst 3DPAFIPN (3 mol%). Then place the tube in a glove box, add 10 mol% of Cs₂CO₃, remove the tube from the glove box, and purge the tube three times under a double-row CO₂ atmosphere. After purging, add 20 mol% of C₆H₂ under a CO₂ stream. 13SH and 2 mL DMAc (ultra-dry solvent) were added; after adding the solvent, the reaction tube was sealed and frozen in liquid nitrogen for 5 minutes, followed by three purgings under a CO2 atmosphere. The reaction tube was placed 1 cm away from 30W blue (wavelength 400~480nm) LEDs and stirred at room temperature for 12 hours. After the reaction was completed, 1.5 equivalents of BzCl were added, and the mixture was stirred at room temperature for 2 hours. Then, 3 mL of 1 N HCl and 3 mL of ethyl acetate were added, and the mixture was stirred for 5 minutes. The mixture was then extracted five times with ethyl acetate. The organic phases were combined and evaporated to dryness using a rotary evaporator. The solid residue was separated by silica gel column chromatography to obtain the target product. α -Amino acids. Specific results are as follows:

[0031] Note: [a] Separation yield. [b] α - Amino acid 2a' was obtained by acidification with 6 mol / L hydrochloric acid. [c] The amide derivative was used as a substrate and no further amidation treatment was performed. [d] 3DPAFIPN (5 mol%) was used, and the reaction time was 24 hours.

[0032] The experimental results above demonstrate that different primary and secondary benzylamines are well compatible. Benzylamines and their derivatives modified with different substituents or functional groups are compatible in this reaction system, including alkyl, phenyl, cyano, fluorine, ester, amide, naphthyl, heteroaryl, etc., and all can be obtained in moderate to excellent yields. α - Amino acid products.

[0033] Example 2: A synthesis based on CH bond carboxylation of amides and their derivatives α The method for treating amino acid compounds is as follows: After drying a 25 mL Schlenk reaction tube equipped with a stirrer under vacuum, 0.2 mmol of amide and its derivatives (if the substrate is solid, add it at this stage; if the substrate is liquid, add it via syringe after adding the solvent) and photocatalyst 4DPAIPN (1 mol%) were added. The tube was then placed in a glove box, and 2 equivalents of Cs₂CO₃ were added. The tube was then removed from the glove box and purged three times under a double-row CO₂ atmosphere. After purging, 2 mL of DMSO (ultra-dry solvent) was added under a CO₂ stream. After adding the solvent, the tube was placed 1 cm away from 30W blue (wavelength 400~480 nm) LEDs and stirred in a 40°C oil bath for 12 hours. After the reaction was complete, 2 mL of 2 N HCl and 3 mL of ethyl acetate were added and stirred for 5 minutes. Then, 10 mL of water was added to the tube, and the mixture was extracted five times with ethyl acetate. The organic phases were combined and evaporated to dryness using a rotary evaporator. The solid residue was separated by silica gel column chromatography to obtain the target product – amino acids. For some substrates, after rotary evaporation, 2 mL of MeOH and 2 mL of Et₂O were added to dissolve them, followed by the addition of 3 equivalents of TMSCHN₂ (a 2 N solution in n-hexane) at 0 °C. After the addition was complete, the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the mixture was evaporated to dryness using a rotary evaporator and separated by silica gel column chromatography to obtain the target product. α -Amino acid methyl ester. Specific results are as follows:

[0034] Note: [a] Standard reaction conditions: 3 (0.2 mmol, 1 eq.), 4DPAIPN (1 mol%), Cs₂CO₃ (2 eq.), DMSO (2 mL), 25 mL reaction tubes, under carbon dioxide (1 atm) irradiation at 40°C for 12 hours. Product yield was determined. [b] 2 mol% 4DPAIPN. [c] 4i:4a = 8.3:1. [d] Used i PrI is used for esterification. [e] Esterification is performed using TMSCHN2. PMP = p-methoxyphenyl.

[0035] The above experimental results show that amides and their derivatives modified with different substituents, regardless of whether they are electron-depleted, electron-rich, or electron-neutral groups, are compatible and can all achieve the desired results in moderate to excellent yields. α - Amino acid products. A variety of functional groups or substituents are compatible in this reaction system, including: alkyl, cyano, halogen, phenyl, methoxy, ester, heteroaryl, etc.

[0036] Example 3: This study used 4-phenylbenzylamine as a template substrate and investigated the effect of changing reaction conditions on the reaction yield. The specific process is as follows:

[0037]

[0038] The structural formulas for 3DPAFIPN, 4DPAIPN, and 4CzIPN are as follows:

[0039] Note: [a] Reaction conditions: 1a (0.2 mmol, 1 eq.), 3DPAFIPN (3 mol%), C6H 13 SH (20 mol%), Cs₂CO₃ (10 mol%), DMAc (2 mL), and 10 mL test tubes were irradiated with a blue LED lamp (30 W, 450 nm) at room temperature (1 atm) for 12 hours, followed by amidation with BzCl (2 eq.) at room temperature, and finally quenched with 1 N hydrochloric acid (aqueous solution). Yields were determined by crude 1H NMR spectroscopy, using 1,3,5-trimethoxybenzene as an internal standard. [b] The fractions in parentheses indicate the separated yields. ND = Not detected, rt = room temperature, DMAc = N,N-dimethylacetamide, DMSO = dimethyl sulfoxide, BzCl = benzoyl chloride.

[0040] The experimental results above show that the separation yield of the corresponding amino acid under the reaction conditions of this invention is as high as 74%. A series of control experiments show that light, photocatalyst, HAT reagent, alkali and CO2 are all crucial. If any one of them is missing, the yield will drop significantly, or even the target product may not be obtained.

[0041] Example 4 This study used N-benzyl-4-methoxybenzamide as a template substrate and investigated the effect of changing reaction conditions on the reaction yield. The specific process is as follows:

[0042]

[0043] PG:

[0044] Note: [a] Reaction conditions: 3a (0.2 mmol, 1 eq), 4DPAIPN (1 mol%), Cs₂CO₃ (2 eq.), DMSO (2 mL), 25 mL test tubes, irradiated at 40 °C for 12 hours under CO₂ (1 atm) conditions using a blue LED lamp (30 W, 450 nm). Yield was determined by crude 1H NMR spectroscopy with CH₂Br₂ as an internal standard. [b] Separation of yield. PMP = p-methoxyphenyl, DMF = N,N-dimethylformamide.

[0045] The experimental results above show that the yield of the corresponding amino acid was 95% under the reaction conditions of this invention. Control experiments indicate that light, photocatalyst, base, and CO2 are all essential for the conversion; the absence of any one of these will significantly reduce the yield, or even prevent the acquisition of the target product. Changing the reaction temperature, the amount of photocatalyst, or the amount of base slightly reduced the yield. Changing the types of key reaction components, such as the photocatalyst, base, or solvent, will lead to a significant decrease in yield.

[0046] The product obtained by this invention was characterized by nuclear magnetic resonance (NMR) and mass spectrometry (MS). The NMR and MS data were consistent with the obtained product. Specific characterization data are as follows: 2-([1,1'-biphenyl]-4-yl)-2-benzamide acetic acid (2a) 49.0 mg, 74%, white solid; R f =0.46 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 12.97 (s, 1H), 9.08 (d, J = 7.4 Hz, 1H), 7.94(d, J = 7.2 Hz, 2H), 7.71 – 7.64 (m, 4H), 7.59 (d, J = 8.1 Hz, 2H), 7.55 (t, J =7.1 Hz, 1H), 7.47 (t, J = 7.5 Hz, 4H), 7.37 (t, J = 7.4 Hz, 1H), 5.66 (d, J = 7.4Hz, 1H). 13 C NMR (101 MHz, DMSO-) d6) δ 171.9, 166.3, 139.84, 139.79, 136.3,133.8, 131.5, 129.0, 128.8, 128.2, 127.7, 127.5, 126.74, 126.71, 56.6.HRMS(ESI+) calcd for C 21 H 18 NO3 + [M+H] + : 332.1281, found 332.1277. 2-([1,1'-biphenyl]-4-yl)-2-(N-methylbenzamido)acetic acid (2b) 38.7 mg, 56%, white solid; R f =0.55 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 7.77 – 7.65 (m, 6H), 7.54 – 7.28 (m, 15H), 6.15 (s, 1H), 5.58 – 5.21 (m, 0.5H), 2.88 – 2.64 (m, 4.5H). 13 C NMR (101 MHz, DMSO- d 6) δ 171.2, 140.0, 139.5, 135.9, 133.7, 129.9, 129.8, 129.0, 128.5,127.7, 127.0, 126.7, 126.2, 60.6, 35.0.HRMS(ESI+) calcd for C 22 H 19 NNaO3 + [M+Na] + :368.1257, found 368.1251.Notes:Rotamers is observed in the 1 H NMR spectrum.One carbonyl signal is missing in the 13 C NMR spectrum, maybe due to overlap with another peak. 2-([1,1'-biphenyl]-4-yl)-2-(N-ethylbenzamido)acetic acid (2c) 21.5 mg, 30%, white solid; R f =0.58 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 7.75 – 7.65 (m, 6H), 7.61 – 7.34 (m, 15H), 5.65 (s, 1H), 5.42 (s, 0.5H), 3.29 – 3.16 (m, 3H), 0.82 (t, J = 7.0 Hz, 4.5H). 13 C NMR(151 MHz, DMSO) δ 171.2, 171.0, 139.8, 139.7, 136.7, 134.9, 130.2,129.5, 129.0, 128.6, 127.7, 126.9, 126.7, 126.1, 61.7, 43.2, 14.7.HRMS(ESI+)calcd for C 23 H 21 NNaO3 + [M+Na] + : 382.1414, found 382.1414.Notes: Rotamers is observed in the 1 H NMR spectrum. 2-([1,1'-biphenyl]-4-yl)-2-(N-isopropylbenzamido)acetic acid (2d) 19.4 mg, 26%, white solid; R f =0.65 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 12.47 (s, 1H), 7.68 (d, J = 7.2 Hz, 2H), 7.62(d, J= 8.2 Hz, 2H), 7.59 – 7.44 (m, 7H), 7.43 – 7.34 (m, 3H), 5.25 (s, 1H), 3.99 (s, 1H), 1.33 – 1.21 (m, 3H), 1.00 – 0.80 (m, 3H). 13 C NMR (101 MHz, DMSO-) d 6) δ 170.8, 170.3, 140.1, 138.7, 137.2, 137.0, 129.4, 129.2, 129.0, 128.7,127.3, 126.6, 125.8, 125.6, 57.5, 51.1, 21.1, 20.2.HRMS(ESI+) calcd forC 24 H 23 NNaO3 + [M+H] + : 396.1570, found 396.1561. 2-Benzamido-2-(4-trifluoromethylphenyl)acetic acid (2e) 36.2 mg, 56%, white solid; R f =0.41 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 13.14 (s, 1H), 9.19 (d, J = 7.5 Hz, 1H), 7.93(d, J = 7.5 Hz, 2H), 7.80 – 7.70 (m, 4H), 7.56 (t, J = 7.2 Hz, 1H), 7.48 (t, J =7.2 Hz, 2H), 5.76 (d, J = 7.5 Hz, 1H). 13 C NMR (101 MHz, DMSO-) d 6) δ 171.3, 166.3,142.1, 133.6, 131.6, 129.0, 128.4 (q, J = 32.0 Hz), 128.3, 127.7, 125.3 (q, J =4.1 Hz), 124.2 (q,J = 272.1 Hz), 56.4. 19 F NMR (376 MHz, DMSO- d 6) δ -61.0.HRMS(ESI+) calcd for C 16 H 12 F3NNaO3 + [M+Na] + : 346.0661, found 346.0665. 2-Benzamido-2-(4-cyanophenyl)acetic acid (2f) 21.3 mg, 38%, white solid; R f =0.29 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 13.18 (s, 1H), 9.20 (d, J = 7.7 Hz, 1H), 7.91(d, J = 6.9 Hz, 2H), 7.86 (d, J = 8.3 Hz, 2H), 7.71 (d, J = 8.3 Hz, 2H), 7.56 (t, J =7.3 Hz, 1H), 7.48 (t, J = 7.4 Hz, 2H), 5.76 (d, J = 7.6 Hz, 1H). 13 C NMR (101 MHz, DMSO- d 6) δ 171.0, 166.3, 143.0, 133.5, 132.3, 131.6, 129.2, 128.3, 127.6,118.7, 110.6, 56.4.HRMS(ESI+) calcd for C 16 H 13 N2O3 + [M+H] + : 281.0921, found281.0926. 2-Benzamido-2-(4-methoxycarbonylphenyl)acetic acid (2g) 43.9 mg, 70%, white solid; Rf =0.20 (DCM / MeOH 10 / 1); MPa: 153-154 ℃; 1 H NMR (400 MHz, DMSO-) d 6) δ 13.11 (s, 1H), 9.16 (d, J = 7.6 Hz, 1H), 7.97(d, J = 8.0 Hz, 2H), 7.92 (d, J = 7.2 Hz, 2H), 7.65 (d, J = 8.0 Hz, 2H), 7.55 (t, J =7.3 Hz, 1H), 7.47 (t, J = 7.5 Hz, 2H), 5.73 (d, J = 7.6 Hz, 1H). 13 C NMR (101 MHz, DMSO- d 6) δ 171.3, 166.3, 166.0, 142.6, 133.6, 131.6, 129.2, 129.1, 128.5,128.2, 127.7, 56.5, 52.2.HRMS(ESI+) calcd for C 17 H 15 NNaO5 + [M+Na] + : 336.0842, found 336.0842. 2-Benzamido-2-(4-ethoxycarbonylphenyl)acetic acid (2h) 47.2 mg, 72%, white solid; R f =0.21 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 9.15 (d, J = 7.6 Hz, 1H), 7.96 (d, J = 8.4 Hz,2H), 7.93 – 7.90 (m, 2H), 7.65 (d, J = 8.4 Hz, 2H), 7.55 (t, J= 7.3 Hz, 1H), 7.47 (t, J = 7.5 Hz, 2H), 5.72 (d, J = 7.6 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 1.32(t, J = 7.1 Hz, 3H). 13 C NMR (101 MHz, DMSO-) d 6) δ 171.3, 166.3, 165.5, 142.6,133.6, 131.6, 129.4, 129.2, 128.5, 128.3, 127.7, 60.8, 56.5, 14.2.HRMS(ESI+)calcd for C 18 H 17 NNaO5 + [M+Na] + : 350.0999, found 350.1001. 2-Benzamido-2-(4-Butylcarbamoylphenyl)acetic acid (2i) 45.2 mg, 64%, white solid; R f =0.15 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 9.09 (d, J = 7.6 Hz, 1H), 8.42 (t, J = 5.7 Hz, 1H), 7.92 (d, J = 7.6 Hz, 2H), 7.83 (d, J = 7.9 Hz, 2H), 7.58 (d, J = 8.0 Hz, 2H), 7.54 (d, J = 7.3 Hz, 1H), 7.47 (t, J = 7.5 Hz, 2H), 5.68 (d, J = 7.5 Hz, 1H), 3.26(q, J = 6.7 Hz, 2H), 1.50 (p, J = 7.2 Hz, 2H), 1.32 (h, J= 7.3 Hz, 2H), 0.90 (t, J =7.3 Hz, 3H). 13 C NMR (101 MHz, DMSO-) d 6) δ 171.6, 166.3, 165.8, 140.1, 134.3,133.7, 131.5, 128.3, 128.0, 127.7, 127.2, 56.5, 31.3, 19.7, 13.7. N CH 2discovered by DMSO residual peak.HRMS(ESI+) calcd for C 20 H 23 N2O4 + [M+H] + : 355.1652, found 355.1655. 2-Benzamido-2-(4-[(4-fluorophenyl)carbamoyl]phenyl)acetic acid (2j) 40.7 mg, 52%, white solid; R f =0.18 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 10.30 (s, 1H), 9.15 (d, J = 7.6 Hz, 1H), 7.94(t, J = 7.1 Hz, 4H), 7.79 (dd, J = 8.9, 5.0 Hz, 2H), 7.67 (d, J = 7.9 Hz, 2H), 7.56(t, J = 7.3 Hz, 1H), 7.48 (t, J = 7.5 Hz, 2H), 7.20 (t, J = 8.7 Hz, 2H), 5.74 (d, J =7.5 Hz, 1H). 13 C NMR (101 MHz, DMSO-) d 6) δ 171.5, 166.3, 165.2, 158.3 (d, J = 240.2Hz), 140.9, 135.5 (d, J= 2.0 Hz), 134.4, 133.7, 131.6, 128.3, 128.2, 127.72,127.70, 122.1 (d, J = 7.8 Hz), 115.2 (d, J = 22.1 Hz), 56.5. 19 F NMR (376 MHz, DMSO- d 6) δ -118.9.HRMS(ESI+) calcd for C 22 H 17 FN2NaO4 + [M+Na] + : 415.1065, found415.1063. 2-Benzamido-2-(4'-(trifluoromethoxy)-[1,1'-biphenyl]-4-yl)acetic acid (2k) 43.9 mg, 53%, white solid; R f =0.44 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 12.95 (s, 1H), 9.11 (d, J = 7.5 Hz, 1H), 7.94(d, J = 7.6 Hz, 2H), 7.80 (d, J = 8.2 Hz, 2H), 7.70 (d, J = 7.9 Hz, 2H), 7.62 (d, J =7.9 Hz, 2H), 7.58 – 7.52 (m, 1H), 7.51 – 7.43 (m, 4H), 5.68 (d, J = 7.4 Hz, 1H). 13 C NMR (101 MHz, DMSO-) d 6) δ 171.8, 166.3, 147.9, 139.1, 138.3, 136.9,133.8, 131.5, 128.8, 128.6, 128.2, 127.7, 126.9, 121.5, 120.1 (q, J = 256.0Hz), 56.5. 19F NMR (376 MHz, DMSO- d 6) δ -56.8.HRMS(ESI+) calcd for C 22 H 16 F3NNaO4 + [M+Na] + : 438.0924, found 438.0922. 2-Benzamido-2-(3,5-bis(trifluoromethyl)phenyl)acetic acid (2l) 50.9 mg, 65%, white solid; R f =0.47 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 13.33 (s, 1H), 9.34 (d, J = 7.8 Hz, 1H), 8.26(s, 2H), 8.09 (s, 1H), 7.91 (d, J = 8.3 Hz, 2H), 7.58 (t, J = 7.3 Hz, 1H), 7.50(t, J = 7.4 Hz, 2H), 5.99 (d, J = 7.8 Hz, 1H). 13 C NMR (101 MHz, DMSO-) d 6) δ 170.9,166.3, 141.2, 133.5, 131.7, 130.2 (q, J = 32.9 Hz), 129.2, 128.4, 127.6, 123.3(q, J = 272.8 Hz), 121.7, 55.7. 19 F NMR (376 MHz, DMSO- d 6) δ -61.3.HRMS(ESI+)calcd for C 17 H 12 F6NO3 + [M+H] + : 392.0716, found 392.0716. 2-Benzamido-2-(3-fluoro-[1,1'-biphenyl]-4-yl)acetic acid (2m) 38.3 mg, 55%, white solid; R f =0.45 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 13.11 (s, 1H), 9.20 (d, J = 7.7 Hz, 1H), 7.94 (d, J = 7.1 Hz, 2H), 7.71 (d, J = 7.3 Hz, 2H), 7.64 (t, J = 8.0 Hz, 1H), 7.60 –7.53 (m, 3H), 7.48 (t, J = 7.5 Hz, 4H), 7.40 (t, J = 7.2 Hz, 1H), 5.96 (d, J = 7.6Hz, 1H). 13 C NMR (101 MHz, DMSO-) d 6) δ 171.1, 166.3, 160.5 (d, J = 246.2 Hz), 142.2(d, J = 8.0 Hz), 138.5, 133.6, 131.6, 130.1 (d, J = 3.9 Hz), 129.0, 128.3, 128.2,127.7, 126.8, 123.7 (d, J = 14.9 Hz), 122.7 (d, J = 2.9 Hz), 113.4 (d, J = 22.9Hz), 50.0. 19 F NMR (376 MHz, DMSO- d 6) δ -117.2.HRMS(ESI+) calcd for C 21 H 16 FNNaO3 + [M+Na] + : 372.1006, found 372.0999. 2-Benzamido-2-(2-fluoro-[1,1'-biphenyl]-4-yl)acetic acid (2n) 60.0 mg, 83%, white solid; R f =0.46 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 13.06 (s, 1H), 9.15 (d, J = 7.6 Hz, 1H), 7.95 (d, J = 7.6 Hz, 2H), 7.60 – 7.39 (m, 11H), 5.73 (d, J = 7.5 Hz, 1H). 13 C NMR (101MHz, DMSO-) d 6) δ 171.4, 166.3, 158.8 (d, J = 246.1 Hz), 139.1 (d, J = 7.9 Hz),134.8, 133.7, 131.6, 130.7 (d, J = 2.8 Hz), 128.8 (d, J = 2.7 Hz), 128.7, 128.3,127.9, 127.8, 127.7, 124.8 (d, J = 2.8 Hz), 115.7 (d, J = 23.9 Hz), 56.1. 19 F NMR (376 MHz, DMSO- d 6) δ -118.4.HRMS(ESI+) calcd for C 21 H 16 FNNaO3 + [M+Na] + : 372.1006, found 372.0998. 2-Benzamido-2-(2,3-difluoro-[1,1'-biphenyl]-4-yl)acetic acid (2o) 38.9 mg, 53%, white solid; R f =0.47 (DCM / MeOH 5 / 1); 1 H NMR (600 MHz, DMSO-) d 6) δ 13.34 (s, 1H), 9.27 (d,J = 7.7 Hz, 1H), 7.94 (d, J = 7.6 Hz, 2H), 7.61 – 7.54 (m, 3H), 7.53 – 7.43 (m, 6H), 7.38 (t, J = 7.7Hz, 1H), 5.98 (d, J = 7.6 Hz, 1H). 13 C NMR (151 MHz, DMSO-) d 6) δ 170.5, 166.2, 148.5 (dd, J = 243.2, 13.7 Hz), 146.9 (dd, J = 243.4, 13.9 Hz), 133.8, 133.4,131.7, 129.9 (d, J = 9.9 Hz), 128.80, 128.77, 128.5, 128.3, 127.6, 126.4 (d, J =12.1 Hz), 125.1, 124.2, 50.0. 19 F NMR (376 MHz, DMSO- d 6) δ -141.9 (d, J = 21.5Hz), -144.4 (d, J = 21.5 Hz).HRMS(ESI+) calcd for C 21 H 15 F2NNaO3 + [M+Na] + : 390.0912, found 390.0907. 2-Benzamido-2-(2,5-difluoro-[1,1'-biphenyl]-4-yl)acetic acid (2p) 53.6 mg, 73%, white solid; R f =0.47 (DCM / MeOH 5 / 1); 1 H NMR (600 MHz, DMSO-) d 6) δ 13.36 (s, 1H), 9.23 (d, J = 7.9 Hz, 1H), 7.94(d, J= 7.5 Hz, 2H), 7.64 – 7.41 (m, 10H), 5.98 (d, J = 7.8 Hz, 1H). 13 C NMR (151MHz, DMSO-) d 6) δ 170.6, 166.2, 156.1 (d, J = 243.3 Hz), 154.9 (d, J = 242.3 Hz),133.7, 133.4, 131.7, 129.4 (dd, J = 14.9, 8.4 Hz), 128.8, 128.7, 128.5, 128.4,127.6, 125.9 (dd, J = 17.2, 7.3 Hz), 116.9 (d, J = 24.9 Hz), 116.6 (d, J = 27.2Hz), 49.7. 19 F NMR (376 MHz, DMSO- d 6) δ -122.5 (d, J = 18.0 Hz), -123.2 (d, J = 17.9Hz).HRMS(ESI+) calcd for C 21 H 15 F2NNaO3 + [M+Na] + : 390.0912, found 390.0907. 2-Benzamido-2-(4-methoxycarbonylphenyl)propionic acid (2q) 33.4 mg, 51%, white solid; R f =0.58 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 8.81 (s, 1H), 7.95 (d, J = 8.6 Hz, 2H), 7.91– 7.87 (m, 2H), 7.69 (d, J = 8.6 Hz, 2H), 7.57 (t, J = 7.3 Hz, 1H), 7.49 (t,J =7.4 Hz, 2H), 3.85 (s, 3H), 1.90 (s, 3H). 13 C NMR (101 MHz, DMSO-) d 6) δ 173.0,166.1, 165.9, 146.7, 134.1, 131.5, 128.8, 128.4, 128.3, 127.5, 127.0, 61.6,52.1, 24.0.HRMS(ESI+) calcd for C 18 H 17 NNaO5 + [M+Na] + : 350.0999, found 350.0995. 2-Benzamido-2-(naphth-2-yl)acetic acid (2r) 32.4 mg, 53%, white solid; R f =0.43 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 12.98 (s, 1H), 9.14 (d, J = 7.4 Hz, 1H), 8.02(s, 1H), 7.97 – 7.89 (m, 5H), 7.66 (dd, J = 8.5, 1.7 Hz, 1H), 7.58 – 7.51 (m,3H), 7.47 (t, J = 7.5 Hz, 2H), 5.78 (d, J = 7.4 Hz, 1H). 13 C NMR (101 MHz, DMSO-) d 6)δ 171.9, 166.3, 134.7, 133.8, 132.7, 132.5, 131.5, 128.2, 128.0, 127.8,127.7, 127.5, 127.0, 126.4, 126.3, 126.2, 57.0.HRMS(ESI+) calcd for C 19 H 15 NNaO3 + [M+Na] + : 328.0944, found 328.0940. 2-Benzamido-2-(benzofuran-2-yl)acetic acid (2s) 23.6 mg, 40%, white solid; R f =0.45 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 13.32 (s, 1H), 9.35 (d, J = 7.5 Hz, 1H), 7.95(d, J = 6.9 Hz, 2H), 7.65 (d, J = 6.9 Hz, 1H), 7.59 (d, J = 8.2 Hz, 1H), 7.55 (d, J =7.3 Hz, 1H), 7.48 (t, J = 7.4 Hz, 2H), 7.32 (td, J = 7.8, 1.5 Hz, 1H), 7.26 (td, J = 7.4, 1.1 Hz, 1H), 6.99 (s, 1H), 5.90 (d, J = 7.5 Hz, 1H). 13 C NMR (101 MHz, DMSO- d 6) δ 169.5, 166.3, 154.2, 152.8, 133.4, 131.7, 128.3, 127.8, 127.7,124.5, 123.0, 121.3, 111.2, 105.4, 51.2.HRMS(ESI+) calcd forC 17 H 13 NNaO4 + [M+Na] + :318.0737, found318.0738. 2-Benzamido-2-(benzo[b]thiophene-2-yl)acetic acid (2t) 47.3 mg, 76%, white solid; R f =0.45 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-)d 6) δ 13.34 (s, 1H), 9.37 (d, J = 7.6 Hz, 1H), 7.98– 7.92 (m, 3H), 7.84 (dd, J = 6.8, 2.2 Hz, 1H), 7.60 – 7.54 (m, 1H), 7.52 –7.46 (m, 3H), 7.40 – 7.31 (m, 2H), 5.94 (d, J = 7.5 Hz, 1H). 13 C NMR (101 MHz, DMSO- d 6) δ 170.6, 166.3, 140.4, 139.2, 139.0, 133.4, 131.7, 128.3, 127.7,124.5, 124.4, 123.6, 123.2, 122.3, 52.9.HRMS(ESI+) calcd for C 17 H 14 NO3S + [M+H] + 312.0689, found 312.0685. 2-(4-Methoxybenzamido)-2-phenylacetic acid (4a) 54.2 mg, 95%, white solid; R f =0.20 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 12.83 (s, 1H), 8.87 (d, J = 7.5 Hz, 1H), 7.92(d, J = 8.8 Hz, 2H), 7.49 (d, J = 6.9 Hz, 2H), 7.42 – 7.29 (m, 3H), 6.99 (d, J =8.9 Hz, 2H), 5.59 (d, J = 7.4 Hz, 1H), 3.81 (s, 3H). 13 C NMR (101 MHz, DMSO-) d6) δ172.1, 165.7, 161.8, 137.3, 129.6, 128.4, 128.1, 127.8, 125.9, 113.4, 56.8,55.4.HRMS(ESI-) calcd for C 16 H 14 NO4 - [MH] - : 284.0928, found 284.0924. 2-Benzamido-2-phenylacetic acid (4b) 43.4 mg, 85%, white solid; R f =0.35 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 12.86 (s, 1H), 9.05 (d, J = 7.5 Hz, 1H), 7.92(d, J = 7.1 Hz, 2H), 7.59 – 7.42 (m, 5H), 7.42 – 7.29 (m, 3H), 5.60 (d, J = 7.4Hz, 1H). 13 C NMR (101 MHz, DMSO-) d 6) δ 171.9, 166.3, 137.2, 133.8, 131.5, 128.4,128.21, 128.16, 127.9, 127.7, 56.9.HRMS(ESI-) calcd for C 15 H 12 NO3 - [MH] - :254.0823, found 254.0819. 2-(4-Methoxybenzamido)-2-(4-Methoxyphenyl)acetic acid (4c) 53.6 mg, 85%, white solid; R f =0.24 (DCM / MeOH 10 / 1); 1 H NMR (400 MHz, DMSO-) d6) δ 12.77 (s, 1H), 8.78 (d, J = 7.4 Hz, 1H), 7.91(d, J = 8.2 Hz, 2H), 7.40 (d, J = 8.2 Hz, 1H), 6.98 (d, J = 8.4 Hz, 2H), 6.93 (d, J =8.2 Hz, 2H), 5.50 (d, J = 7.2 Hz, 1H), 3.81 (s, 3H), 3.75 (s, 3H). 13 C NMR (101MHz, DMSO-) d 6) δ 172.8, 166.1, 162.2, 159.4, 130.1, 129.9, 129.6, 126.5,114.2, 113.8, 56.7, 55.8, 55.6.HRMS(ESI+) calcd for C 17 H 17 NNaO5 + [M+Na] + :338.0999, found 338.0995. 2-(4-Methoxybenzamido)-2-(4-(trifluoromethoxy)phenyl)acetic acid (4d) 69.4 mg, 94%, white solid; R f =0.54 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 13.02 (s, 1H), 8.96 (d, J = 7.5 Hz, 1H), 7.91(d, J = 8.9 Hz, 2H), 7.62 (d, J = 8.7 Hz, 2H), 7.38 (d, J = 8.8 Hz, 2H), 7.00 (d, J =8.9 Hz, 2H), 5.65 (d, J = 7.4 Hz, 1H), 3.81 (s, 3H). 13 C NMR (101 MHz, DMSO-)d 6) δ171.8, 165.8, 161.9, 148.0, 137.0, 130.2, 129.7, 125.9, 121.0, 120.2 (q, J =256.2 Hz), 113.5, 56.1, 55.4. 19 F NMR (376 MHz, DMSO- d 6) δ -56.8.HRMS(ESI+)calcd for C 17 H 14 F3NNaO5 + [M+Na] + : 392.0716, found 392.0712. 2-(4-Cyanophenyl)-2-(4-Methoxybenzamido)acetic acid (4e) 61.4 mg, 99%, white solid; R f =0.29 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 13.15 (s, 1H), 9.05 (d, J = 7.7 Hz, 1H), 7.91(d, J = 8.7 Hz, 2H), 7.86 (d, J = 7.9 Hz, 2H), 7.70 (d, J = 8.0 Hz, 2H), 7.01 (d, J =8.8 Hz, 2H), 5.74 (d, J = 7.5 Hz, 1H), 3.81 (s, 3H). 13 C NMR (101 MHz, DMSO-) d 6) δ171.6, 166.1, 162.4, 143.7, 132.7, 130.0, 129.6, 126.2, 119.2, 114.0, 111.0,56.8, 55.9.HRMS(ESI+) calcd forC 17 H 14 N2NaO4 + [M+Na] + : 333.0846, found 333.0850. 2-(4-Methoxybenzamido)-2-(4-(methoxycarbonyl)phenyl)acetic acid (4f) 66.6 mg, 97%, white solid; R f =0.45 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 9.01 (d, J = 7.6 Hz, 1H), 7.97 (d, J = 8.0 Hz, 2H), 7.92 (d, J = 8.4 Hz, 2H), 7.64 (d, J = 8.0 Hz, 2H), 7.00 (d, J = 8.7 Hz, 2H), 5.71 (d, J = 7.5 Hz, 1H), 3.85 (s, 3H), 3.81 (s, 3H). 13 C NMR (101 MHz, DMSO-) d 6) δ171.5, 166.0, 165.7, 161.9, 142.8, 129.6, 129.2, 129.0, 128.5, 125.8, 113.5,56.5, 55.4, 52.2.HRMS(ESI+) calcd for C 18 H 17 NNaO6 + [M+Na] + : 366.0948, found366.0945. 2-(4-Methoxybenzamido)-2-(4-(Methanesulfonyl)phenyl)acetic acid (4g) 64.7 mg, 89%, white solid; R f =0.21 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 9.05 (d, J = 7.6 Hz, 1H), 7.93 (t, J = 8.8 Hz, 4H), 7.77 (d, J= 8.1 Hz, 2H), 7.01 (d, J = 8.8 Hz, 2H), 5.76 (d, J = 7.5 Hz, 1H), 3.81 (s, 3H), 3.22 (s, 3H). 13 C NMR (101 MHz, DMSO-) d 6) δ 171.3, 165.7, 161.9,143.4, 140.2, 129.6, 129.1, 127.1, 125.7, 113.5, 56.3, 55.4, 43.5.HRMS(ESI+)calcd for C 17 H 17 NNaO6S + [M+Na] + : 386.0669, found 386.0665. 2-(3-Fluorophenyl)-2-(4-Methoxybenzamido)acetic acid (4h) 54.0 mg, 89%, white solid; R f =0.42 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 8.95 (d, J = 7.6 Hz, 1H), 7.92 (d, J = 8.8 Hz,2H), 7.46 – 7.39 (m, 1H), 7.38 – 7.32 (m, 2H), 7.21 – 7.12 (m, 1H), 7.00 (d, J = 8.9 Hz, 2H), 5.65 (d, J = 7.6 Hz, 1H), 3.81 (s, 3H). 13 C NMR (101 MHz, DMSO-) d 6)δ 171.6, 165.7, 162.0 (d, J = 243.3 Hz), 161.9, 140.1 (d, J = 7.4 Hz), 130.3 (d, J = 8.4 Hz), 129.6, 125.8, 124.4 (d, J= 2.7 Hz), 114.9 (d, J = 22.7 Hz), 114.7 (d, J = 21.6 Hz), 113.5, 56.2, 55.4. 19 F NMR (376 MHz, DMSO- d 6) δ -113.2.HRMS(ESI+)calcd for C 16 H 14 FNNaO4 + [M+Na] + : 326.0799, found 326.0797. 2-(3-Chlorophenyl)-2-(4-methoxybenzamido)acetic acid (4i) 48.0 mg, 75%, white solid; R f =0.53 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 8.97 (d, J = 7.6 Hz, 1H), 7.91 (d, J = 8.8 Hz,2H), 7.58 (s, 1H), 7.49 – 7.45 (m, 1H), 7.42 – 7.39 (m, 2H), 7.00 (d, J = 8.8Hz, 2H), 5.64 (d, J = 7.6 Hz, 1H), 3.81 (s, 3H). 13 C NMR (101 MHz, DMSO-) d 6) δ171.6, 165.7, 161.9, 139.9, 133.0, 130.3, 129.6, 128.4, 128.2, 127.9, 127.8,127.1, 125.8, 113.5, 56.2, 55.4.HRMS(ESI+) calcd for C 16 H 14 ClNNaO4 + [M+Na] +:342.0504, found 342.0509.Notes:The ratio of4hto4ais about 8.3:1, and twoadditional aromatic signals in the 13 The C NMR spectra are from 4a. 2-(4-Methoxybenzamido)-2-(3-(trifluoromethyl)phenyl)acetic acid (4j) 54.4 mg, 77%, white solid; R f =0.55 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 9.06 (d, J = 7.6 Hz, 1H), 7.91 (d, J = 8.7 Hz,2H), 7.88 (s, 1H), 7.81 (d, J = 7.7 Hz, 1H), 7.70 (d, J = 7.8 Hz, 1H), 7.62 (t, J =7.7 Hz, 1H), 7.01 (d, J = 8.5 Hz, 2H), 5.75 (d, J = 7.5 Hz, 1H), 3.81 (s, 3H). 13 CNMR (101 MHz, DMSO- d 6) δ 171.6, 165.7, 161.9, 139.1, 132.5, 129.6, 129.5,129.1 (q, J = 31.6 Hz), 125.8, 124.7 (q, J = 3.7 Hz), 124.6 (q, J = 2.5 Hz), 124.2(q, J = 272.3 Hz), 113.5, 56.2, 55.4. 19 F NMR (376 MHz, DMSO- d 6) δ -61.0.HRMS(ESI+) calcd for C 17 H 14 F3NNaO4+ [M+Na] + 376.0767, found 376.0768. 2-(4-Methoxybenzamido)-2-(o-Tolyl)acetic acid (4k) 58.7 mg, 98%, white solid; R f =0.22 (DCM / MeOH 10 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 8.81 (d, J = 7.5 Hz, 1H), 7.91 (d, J = 8.4 Hz, 2H), 7.39 (d, J = 5.7 Hz, 1H), 7.25 – 7.16 (m, 3H), 6.98 (d, J = 8.8 Hz, 2H), 5.79 (d, J = 7.4 Hz, 1H), 3.80 (s, 3H), 2.38 (s, 3H). 13 C NMR (101 MHz, DMSO-) d 6) δ172.4, 165.7, 161.8, 136.5, 135.9, 130.2, 129.6, 127.8, 127.5, 126.0, 125.9,113.4, 55.4, 53.4, 19.0.HRMS(ESI+) calcd for C 17 H 17 NNaO4 + [M+Na] + : 322.1050, found 322.1045. 2-(5-fluoro-2-methoxyphenyl)-2-(4-methoxybenzamido)acetic acid (4l) 156.6 mg, 94%, white solid; R f =0.24 (DCM / MeOH 10 / 1); 1 H NMR (600 MHz, DMSO-) d 6) δ 12.83 (s, 1H), 8.74 (d, J= 8.0 Hz, 1H), 7.89(d, J = 8.4 Hz, 2H), 7.26 (dd, J = 9.4, 3.2 Hz, 1H), 7.14 (td, J = 8.6, 3.2 Hz, 1H), 7.05 (dd, J = 9.1, 4.5 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 5.96 (d, J = 7.9 Hz, 1H), 3.81 (s, 6H). 13 C NMR (151 MHz, DMSO-) d 6) δ 171.8, 165.6, 161.8, 156.1 (d, J =235.8 Hz), 153.2, 129.5, 127.6, 125.9, 115.3 (d, J = 24.3 Hz), 115.0 (d, J = 22.6Hz), 113.5, 112.6 (d, J = 8.2 Hz), 56.4, 55.4, 50.4. 19 F NMR(376 MHz, DMSO) δ -123.8.HRMS(ESI-) calcd for C 17 H 15 FNO5 - [MH] - : 332.0940, found 332.0939. 2-(4-Methoxybenzamido)-2-phenylpropionic acid (4m) 43.1 mg, 72%, white solid; R f =0.22 (DCM / MeOH 10 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 12.59 (s, 1H), 8.54 (s, 1H), 7.87 (d, J = 8.8Hz, 2H), 7.54 (d, J = 7.3 Hz, 2H), 7.36 (t, J= 7.4 Hz, 2H), 7.29 (t, J = 7.3 Hz, 1H), 7.00 (d, J = 8.8 Hz, 2H), 3.81 (s, 3H), 1.87 (s, 3H). 13 C NMR (101 MHz, DMSO-) d 6) δ 173.6, 165.5, 161.7, 141.3, 129.4, 127.9, 127.2, 126.49, 126.47, 113.5,61.4, 55.4, 23.7.HRMS(ESI+) calcd for C 17 H 17 NNaO4 + [M+Na] + : 322.1050, found322.1051. 2-(4-Methoxybenzamido)-2,2-diphenylacetic acid (4n) 68.7 mg, 95%, white solid; R f =0.48 (DCM / MeOH 10 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 13.02 (s, 1H), 8.93 (s, 1H), 7.89 (d, J = 8.5Hz, 2H), 7.49 – 7.44 (m, 4H), 7.35 – 7.23 (m, 6H), 7.00 (d, J = 8.6 Hz, 2H), 3.81 (s, 3H). 13 C NMR (101 MHz, DMSO-) d 6) δ 172.1, 165.6, 161.9, 141.1, 129.7,128.4, 127.5, 127.1, 126.3, 113.5, 68.5, 55.4.HRMS(ESI+) calcd for C 22 H 19 NNaO4 + [M+Na] + : 384.1206, found 384.1202. 2-(4-Methoxybenzamido)-2-(naphth-1-yl)acetic acid (4o) 63.7 mg, 95%, white solid; R f =0.51 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 12.96 (s, 1H), 9.03 (d, J = 7.6 Hz, 1H), 8.11(d, J = 8.3 Hz, 1H), 8.02 – 7.89 (m, 4H), 7.64 – 7.51 (m, 4H), 6.98 (d, J = 8.5Hz, 2H), 6.40 (d, J = 7.5 Hz, 1H), 3.79 (s, 3H). 13 C NMR (101 MHz, DMSO-) d 6) δ172.5, 165.7, 161.8, 133.5, 133.2, 131.2, 129.7, 128.7, 128.6, 126.7, 125.9,125.8, 125.4, 123.4, 113.4, 55.4, 53.3.HRMS(ESI+) calcd forC 20 H 18 NO4 + [M+H] + :336.1230, found 336.1234. Note: In 13 In a C NMR spectrum, an aromatic signal may go undetected because it overlaps with another peak.

[0047] 2-(4-methoxybenzamido)-2-(pyridin-3-yl)methyl acetate (4p) 28.9 mg, 44%, white solid; R f =0.70 (DCM / MeOH 20 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 9.07 (d, J= 7.1 Hz, 1H), 8.67 (s, 1H), 8.56(s, 1H), 7.93 – 7.85 (m, 3H), 7.44 (dd, J = 8.1, 4.6 Hz, 1H), 7.01 (d, J = 8.8Hz, 2H), 5.66 (d, J = 7.0 Hz, 1H), 4.96 (hept, J = 6.2 Hz, 1H), 3.81 (s, 3H), 1.21 (d, J = 6.3 Hz, 3H), 1.08 (d, J = 6.2 Hz, 3H). 13 C NMR (101 MHz, DMSO-) d 6) δ169.6, 166.0, 161.9, 149.4, 149.1, 135.8, 132.5, 129.6, 125.6, 123.6, 113.5,68.8, 55.4, 54.9, 21.5, 21.3.HRMS(ESI+) calcd for C 18 H 21 N2O4 + [M+H] + : 329.1496, found 329.1501. 2-(furan-2-yl)-2-(4-methoxybenzamido)acetic acid (4q) 43.5 mg, 79%, white solid; R f =0.47 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 9.01 (d, J = 7.7 Hz, 1H), 7.92 (d, J = 8.9 Hz, 2H), 7.66 (dd, J = 1.8, 1.0 Hz, 1H), 6.99 (d, J = 8.9 Hz, 2H), 6.50 – 6.43 (m,2H), 5.70 (d, J = 7.6 Hz, 1H), 3.81 (s, 3H). 13C NMR (101 MHz, DMSO-) d 6) δ 170.2,165.7, 161.9, 149.8, 142.8, 129.7, 125.7, 113.5, 110.7, 108.6, 55.4,50.8.HRMS(ESI ¯ calcd for C 15 H 10 F3O3 ¯ [MH] ¯ : 274.0721, found 274.0718. 2-(4-Methoxybenzamido)-2-(thiophen-3-yl)acetic acid (4r) 47.2 mg, 81%, white solid; R f =0.49 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 12.85 (s, 1H), 8.89 (d, J = 7.7 Hz, 1H), 7.92(d, J = 8.8 Hz, 2H), 7.60 – 7.57 (m, 1H), 7.53 (dd, J = 5.0, 3.0 Hz, 1H), 7.24(dt, J = 5.0, 1.2 Hz, 1H), 7.00 (d, J = 8.9 Hz, 2H), 5.69 (d, J = 7.7 Hz, 1H), 3.81 (s, 3H). 13 C NMR (101 MHz, DMSO-) d 6) δ 171.9, 165.8, 161.8, 137.3, 129.7, 127.7,126.3, 125.9, 123.7, 113.4, 55.4, 52.6.HRMS(ESI ¯ calcd for C 15 H 10 F3O3 ¯ [MH] ¯ :290.0493, found 290.0489. 2-(benzo[b]thiophene-3-yl)-2-(4-methoxybenzamido)acetic acid (4S) 45.1 mg, 66%, white solid; R f =0.46 (DCM / MeOH 5 / 1); 1 H NMR (400 MHz, DMSO-) d 6) δ 8.99 (d, J = 7.4 Hz, 1H), 8.02 (d, J = 7.5 Hz, 1H), 7.91 (d, J = 8.1 Hz, 3H), 7.78 (s, 1H), 7.41 (p, J = 6.9 Hz, 2H), 6.99 (d, J =8.4 Hz, 2H), 6.01 (d, J = 7.3 Hz, 1H), 3.80 (s, 3H). 13 C NMR (101 MHz, DMSO-) d 6) δ171.5, 165.9, 161.8, 139.6, 137.8, 131.6, 129.6, 125.9, 125.8, 124.6, 124.4,122.9, 122.1, 113.4, 55.4, 51.1.HRMS(ESI+) calcd for C 18 H 15 NNaO4S + [M+Na] + 364.0614, found 364.0617. Methyl 3-(tert-butylamino)-2-(4-methoxybenzamido)-3-oxopropionic acid (4t) 44.5 mg, 69%, white solid; R f =0.46 (PE / EA 1 / 1); 1 H NMR (400 MHz, CDCl3) δ 7.83 (d, J = 8.8 Hz, 2H), 7.35 (d, J = 6.4 Hz, 1H), 6.93 (d, J= 8.8 Hz, 2H), 6.44 (s, 1H), 5.15 (d, J = 6.4 Hz, 1H), 3.85 (s, 3H), 3.82 (s, 3H), 1.36 (s, 9H). 13 C NMR(101 MHz, CDCl3) δ 168.8, 166.7, 163.7,162.8, 129.3, 125.5, 114.0, 57.7, 55.6, 53.4, 52.3, 28.7.HRMS(ESI+) calcd forC 16 H 22 N2NaO5 + [M+Na] + : 345.1421, found 345.1416. Methyl 3-((2,3-dihydrobenzo[b][1,4]dioxin-6-yl)amino)-2-(4-methoxybenzamido)-3-oxopropionic acid ester (4u) 46.4 mg, 58%, white solid; R f =0.34 (PE / EA 1 / 1); 1 H NMR (400 MHz, CDCl3) δ 8.68 (s, 1H), 7.84 (d, J = 8.8 Hz, 2H), 7.43(d, J = 6.7 Hz, 1H), 7.17 (d, J = 2.5 Hz, 1H), 6.98 – 6.89 (m, 3H), 6.79 (d, J =8.8 Hz, 1H), 5.46 (d, J = 6.7 Hz, 1H), 4.25 – 4.20 (m, 4H), 3.86 (s, 3H), 3.85(s, 3H). 13 C NMR(101 MHz, CDCl3) δ 168.3, 167.2, 163.2, 163.0, 143.6, 141.0,131.1, 129.4, 125.2, 117.3, 114.1, 113.7, 109.9, 64.5, 64.4, 57.9, 55.6,53.6.HRMS(ESI+) calcd for C 20 H20 N2NaO7 + [M+Na] + : 423.1163, found 423.1164. 2-Cyano-2-(4-methoxybenzamido)methyl acetate (4v) 25.3 mg, 51%, white solid; R f =0.45 (PE / EA 1 / 1); 1 H NMR (400 MHz, CDCl3) δ 7.80 (d, J = 8.8 Hz, 2H), 7.03 (d, J = 7.5 Hz, 1H), 6.94 (d, J = 8.8 Hz, 2H), 5.74 (d, J = 7.5 Hz, 1H), 3.93 (s, 3H), 3.86 (s, 3H). 13 C NMR(101 MHz, CDCl3) δ 166.4, 164.4, 163.4, 129.6, 124.1, 114.24,114.21, 55.6, 54.7, 43.3.HRMS(ESI+) calcd for C 12 H 13 N2O4 + [M+H] + : 249.0870, found249.0874. 2-[(tert-Butoxycarbonyl)amino]-2-(4-{[2-({2-[(S)-2-(methoxycarbonylamino)-4-methylpentamido]acetamido}acetamido)methyl]formamido}phenyl)acetic acid(4w) 51.1 mg, 48%, white solid; R f =0.28 (DCM / MeOH 5 / 1); 1H NMR(400 MHz, DMSO-d6) δ 8.90 (t, J = 5.8 Hz, 1H), 8.29 – 8.16 (m,2H), 7.81 (d, J = 7.9 Hz, 2H), 7.43 (d, J = 7.9 Hz, 2H), 6.73 (d, J = 6.5 Hz,1H), 4.80 (d, J = 6.7 Hz, 1H), 4.33 – 4.23 (m, 1H), 3.87 (d, J = 5.7 Hz, 2H), 3.74 (d, J = 5.8 Hz, 2H), 3.60 (s, 3H), 1.66 – 1.55 (m, 2H), 1.53 – 1.46 (m,1H), 1.35 (s, 3H), 0.86 (d, J = 6.0 Hz, 3H), 0.82 (d, J = 6.1 Hz, 3H). 13 C NMR(101 MHz, DMSO) δ 172.9, 172.0, 169.4, 169.1, 166.7, 154.4, 145.3, 132.1,127.0, 126.7, 78.1, 60.8, 59.5, 51.9, 50.3, 43.0, 41.7, 32.6, 31.4, 29.2,29.1, 28.8, 28.3, 27.9, 26.6, 25.6, 24.2, 22.8, 22.2, 21.4, 14.0.HRMS(ESI+)calcd for C 25 H 36 N4O9 + [M+Na] + : 559.2374, found 559.2366. The above description is only a preferred embodiment of the present invention and is not intended to limit the present invention. Any modifications, equivalent substitutions, improvements, etc., made within the spirit and principles of the present invention should be included within the protection scope of the present invention.

Claims

1. A method for synthesizing an amino acid compound, characterized in that, Includes the following steps: Benzylamine and its derivatives, a photocatalyst, and a base were mixed, and then HAT reagent and a solvent were added under a CO2 atmosphere to obtain a reaction solution. The reaction solution was stirred under light and room temperature conditions, and then the reaction product was acidified and purified to obtain an amino acid compound. Alternatively, amides and their derivatives, photocatalysts, and bases can be mixed, and then a solvent can be added under a CO2 atmosphere to obtain a reaction solution. The reaction solution can be stirred under light and heating conditions, and then the reaction products can be acidified and purified to obtain amino acid compounds. The general structural formulas of the benzylamine and its derivatives are shown in Formula (I), and the general structural formulas of the amide and its derivatives are shown in Formula (II): Among them, R 1 and R 2 Both are hydrogen and C 1-20 Alkyl, aryl and their substituted aryl, heteroaryl, ester, amide, cyano, halogen or carbonyl; R 3 For hydrogen, C 1-20 Alkyl or acyl; R 4 and R 5 Both are hydrogen and C 1-20 Alkyl, alkoxy, acyl, cyano, ester, halogen, aryl and their substituted aryl, heteroaryl or carbonyl; R 6 C 1-20 Alkyl, aryl, or alkoxy; The reaction formula is as follows: 。 2. The method for synthesizing amino acid compounds according to claim 1, characterized in that, R 1 and R 2 All are phenyl groups substituted with hydrogen, biphenyl, trifluoromethyl, cyano, carboxymethyl, or carboxyethyl. , Trifluoromethoxy-substituted biphenyl, halogen-substituted biphenyl, methyl, naphthyl, benzofuranyl, benzothiopheneyl; R 3 It can be hydrogen, benzoyl, methyl, ethyl, or propyl.

3. The method for synthesizing amino acid compounds according to claim 2, characterized in that, The specific structures of benzylamine and its derivatives are as follows: 。 4. The method for synthesizing amino acid compounds according to claim 1, characterized in that, R 4 and R 5 All of these are hydrogen-, phenyl, methoxy-substituted phenyl, trifluoromethoxy-substituted phenyl, cyano-substituted phenyl, carboxymethyl-substituted phenyl, methanesulfonyl-substituted phenyl, halogen-substituted phenyl, trifluoromethyl-substituted phenyl, methyl-substituted phenyl, methyl, naphthyl, pyridyl, furanyl, thiophene, benzothiophene, cyano ; R 6 For p-methoxyphenyl, phenyl, .

5. The method for synthesizing amino acid compounds according to claim 4, characterized in that, The specific structures of amides and their derivatives are as follows: 。 6. The method for synthesizing amino acid compounds according to claim 1, characterized in that, The molar ratio of benzylamine and its derivatives, photocatalyst, base and HAT reagent is 1:0.0001~0.5:0.01~10:0.01~1; the molar ratio of the amide and its derivatives, photocatalyst and base is 1:0.0001~0.5:0.1~10.

7. The method for synthesizing amino acid compounds according to claim 1 or 6, characterized in that, The photocatalyst is an organic dye or an organometallic complex.

8. The method for synthesizing amino acid compounds according to claim 7, characterized in that, The photocatalyst is either a DA-type photocatalyst or an Ir-type photocatalyst.

9. The method for synthesizing amino acid compounds according to claim 8, characterized in that, The photocatalysts are 4CzIPN, 4DPAIPN, 3DPAFIPN, 3DPAFIPN-OMe, 3DPA2FBN, 5CzBN, 4CzPN, DPZ, 4CzPN-Ph, 4CzPN-Bu, 4CzTPN, 4CzTPN-Bu, Ir(dFCF3ppy)2(dtbbpy)PF6, fac -Ir(dF(ppy)3), fac At least one of -Ir(ppy)3 and Ir(ppy)2(dtbbpy)PF6.

10. The method for synthesizing amino acid compounds according to claim 1 or 6, characterized in that, The base is a tert-butanol salt, carbonate, bicarbonate, fluoride salt, phosphate, hydrogen phosphate, carboxylate, or organic base; the HAT reagent is an organic sulfur compound; the solvent is NMP, DMSO, DMF, DMAc, THF, DCM, MeOH, or MeCN; the light irradiation is visible light with a wavelength of 300–700 nm; the stirring time at room temperature is 8–36 h; the stirring temperature under heating conditions is 20–60 ℃, and the stirring time is 4–24 h.

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