Chiral alpha-amino acid with C3 symmetrical structure as well as preparation method and application of chiral alpha-amino acid

Abstract

The invention discloses a chiral alpha-amino acid with a C3 symmetric structure and a preparation method and application thereof, the chiral alpha-amino acid with the C3 symmetric structure provided by the invention is used as an ion pair catalyst, and the structure of the chiral alpha-amino acid with the C3 symmetric structure is more stable than that of other ion pair catalysts due to the C3 symmetric structure; and meanwhile, the chiral phosphamide compound is successfully constructed with relatively high yield (70-80%) and enantioselectivity (80-95%), so that the chiral phosphamide compound has excellent catalytic performance, and the problem that the chiral phosphamide compound is difficult to construct by a traditional ion pair catalyst is solved.

Description

(I) TECHNICAL FIELD

[0001] The present application belongs to the technical field of organic catalysis, and particularly relates to a chiral alpha-amino acid with C3 symmetry structure and a preparation method and application thereof. (II) BACKGROUND

[0002] The essence of chemical reactions involves dynamic changes in the polarity of molecular charge, especially in the transformation process involving charged intermediates. How to accurately control the stereochemical results of the reaction path is a major challenge. The strategy of directional control of transition state absolute configuration through ion pair interaction provides a highly potential solution to this problem. This strategy cooperatively regulates the spatial orientation of reaction intermediates through electrostatic interaction and steric effect, thereby achieving efficient construction of product stereostructure, and showing significant advantages in the synthesis of complex chiral molecules. This non-covalent interaction guided catalytic mode opens up new possibilities for green chemistry and drug synthesis.

[0003] Compounds with rotational symmetry have become a hot topic in asymmetric synthesis research due to their ability to reduce the number of reaction transition states and improve enantioselectivity. Among them, C3 symmetric molecules are particularly prominent and have been applied in the fields of catalysts, ligands, molecular receptors, and metal-organic materials (MOMs). Organic catalysts constructed with C3 symmetry precisely regulate the stereochemical path of the reaction through three sets of equal catalytic units, significantly improving the efficiency of chiral synthesis, and have become a key development direction of asymmetric catalytic systems. In 2006, Du Daming's group successfully synthesized a series of novel chiral C3 symmetric tri(β-hydroxy phosphoramide) ligands and applied them to the asymmetric synthesis of chiral secondary alcohols. In 2010, Moorthy and his colleagues designed and synthesized C3 symmetric tripod-type organic catalysts based on 1,3,5-trialkylbenzene with receptor characteristics and demonstrated their high diastereoselectivity and enantioselectivity in the Michael addition reaction of carbonyl compounds with β-nitrostyrene. In the same year, Hiroshi Fujoka et al. designed a new C3 symmetric tri-imidazoline organic catalyst and found that it could catalyze the asymmetric conjugate addition reaction of β-keto ester and nitroalkene.

[0004] Chiral amino acid catalysts can directly construct precise chiral environments with natural chiral skeletons, avoiding racemization problems. The amino, carboxyl, and side chain groups can be used to introduce multiple interaction sites such as hydrogen bonds and ion pairs, dynamically regulating the stereochemical path of the reaction. Moreover, as a renewable resource, amino acids have the characteristics of abundant raw materials, low cost, and high industrialization adaptability, providing a new solution for asymmetric catalysis. Professor Li Konglong's team successfully prepared a new spiral polyphenyl isocyanate with an L-leucine pendant in 2024 and successfully applied it in the Aldol reaction.

[0005] Imidazolium salt cationic catalysts have many advantages in asymmetric catalysis. N + The cationic center can enhance the acidity of the hydrogen at the 2-position of the imidazole ring, which can act as a hydrogen bond donor to strengthen substrate recognition and stereocontrol. At the same time, its strong coordination ability and controllable electronic effect can stabilize the metal active center and precisely control the stereo selectivity of the reaction to achieve efficient enantiomeric synthesis. By modifying the substituents of the imidazole ring, it can adapt to the complex reaction requirements of dynamic kinetic resolution, light-driven chiral synthesis, etc. In 2016, Professor Chen Junfeng's team successfully realized the high enantioselective phase transfer alkylation of several types of substrates including dihydrocoumarin using a phase transfer catalyst of pentazolium salt. In addition, Academician Tao Yongjiang's team innovatively constructed a new type of chiral spiro-pyrrolyl amide-derived triazole organic cation catalyst, and realized the enantioselective construction of adjacent quaternary carbon centers and the first asymmetric total synthesis of (-)-chimonanthidine. (III)SUMMARY

[0006] The purpose of the present application is to provide a chiral α-amino acid with C3 symmetry structure and its preparation method and application. The chiral α-amino acid with C3 symmetry structure takes uniform tribromobenzene as the core skeleton, and has a chiral pocket structure through the derivatization design of amino acid-imidazole structure. The imidazole ion forms a trivalent bromide salt as an ionic center, which is more stable in structure as an ionic pair catalyst and has a positive effect on promoting the development of ionic pair catalysts. The preparation and synthesis method is simple, and the raw materials are simple and easy to obtain, which provides a basis for developing more similar catalysts in the future. The chiral phosphoramidate compound has excellent catalytic performance in construction, and solves the problem that traditional ionic pair catalysts are difficult to construct chiral phosphoramidate compounds.

[0007] The technical scheme adopted by the present application is:

[0008] In a first aspect, the present application provides a chiral α-amino acid with C3 symmetry structure shown in formula I:

[0009]

[0010] In formula I, R 1 Each independently is isobutyl, neopentyl, phenethyl, isopropyl, methyl, propyl, n-butyl, 2-methylthiomethyl.

[0011] Furthermore, the chiral α-amino acid with C3 symmetry structure shown in formula I is one of the following:

[0012]

[0013]

[0014] In a second aspect, the present application provides a method for preparing the chiral α-amino acid, which comprises the following steps:

[0015] (1) A reaction bottle is added with dichloromethane (DCM), and then sequentially added with compound B (BOC-L-leucine), compound A, 1-hydroxybenzotriazole (HOBt), N, N-diisopropylethylamine (DIPEA), and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride. After stirring at room temperature for 12 hours, the solvent is removed by rotary evaporation under reduced pressure, and then column chromatography on silica gel is performed. The eluent is dichloromethane / methanol (30:1 by volume ratio), and the pressure is applied for elution. The effluent is monitored by thin layer chromatography using dichloromethane / methanol (30:1 by volume ratio) as the developing agent. The components with Rf values of 0.7-0.8 are collected, and the solvent is removed by rotary evaporation under reduced pressure to obtain a light yellow liquid, which is compound C;

[0016] (2) Compound C is added into a reaction bottle, dissolved in dichloromethane, and then slowly dripped with trifluoroacetic acid (TFA). After stirring at room temperature for 12 hours, the stirring is stopped, and the organic phase is extracted with saturated NaHCO3 aqueous solution and dichloromethane for three times, respectively. After the solvent is removed by rotary evaporation under reduced pressure, column chromatography on silica gel is performed. The eluent is dichloromethane / methanol (50:1 by volume ratio), and the pressure is applied for elution. The effluent is monitored by thin layer chromatography using dichloromethane / methanol (10:1 by volume ratio) as the developing agent. The components with Rf values of 0.4-0.5 are collected, and the solvent is removed by rotary evaporation under reduced pressure to obtain a light yellow liquid, which is compound D;

[0017] (3) A reaction bottle is added with a 40% aqueous solution of glyoxal and a 37% aqueous solution of formaldehyde, and then added with methanol. Another beaker is taken, added with compound D and ammonium acetate, and then added with methanol for dissolution. The above-mentioned reaction bottle is slowly dripped with the solution, and then stirred at room temperature for 12 hours. After the solvent is removed by rotary evaporation under reduced pressure, dichloromethane and anhydrous sodium sulfate are added to remove water. After filtration, the filtrate is subjected to column chromatography on silica gel. The eluent is dichloromethane / methanol (50:1 by volume ratio), and the pressure is applied for elution. The effluent is monitored by thin layer chromatography using dichloromethane / methanol (20:1 by volume ratio) as the developing agent. The components with Rf values of 0.4-0.6 are collected, and the solvent is removed by rotary evaporation under reduced pressure to obtain a light yellow liquid, which is compound E;

[0018] (4) Place compound E in a reaction flask, add compound F (tribromobenzyl), then add m-xylene to dissolve, stir at 150°C for 24 h, after the reaction is finished, remove the solvent by rotary evaporation under reduced pressure, and then perform silica gel column chromatography. Use dichloromethane / methanol at a volume ratio of 15:1 as the eluent and elute under pressure. Use dichloromethane / methanol at a volume ratio of 10:1 as the developing solvent for thin-layer chromatography monitoring. Collect the fraction with an Rf value of 0.3-0.4, concentrate to dryness under reduced pressure, remove the solvent by rotary evaporation under reduced pressure to obtain a white solid, which is the chiral α-amino acid shown in Formula I;

[0019]

[0020] R in compound B 1 The compounds are isobutyl, neopentyl, phenethyl, isopropyl, methyl, propyl, n-butyl, and 2-methylthiomethyl; R in compounds C, D, E, and I. 1 In compound B, R 1 .

[0021] Further, in step (1), the molar ratio of compound A to compound B is 1:1-2 (preferably 1:1.05); the molar ratio of compound A to 1-hydroxybenzotriazole, N,N-diisopropylethylamine, and 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride is 1:1-2 (preferably 1:1.5); and the volume of dichloromethane solvent used is 2-2.5 mL / mmol (preferably 2.5 mL / mmol) based on the molar amount of compound A.

[0022] Furthermore, in step (2), the molar ratio of compound C to trifluoroacetic acid is 1:5-10 (preferably 1:6); the volume of dichloromethane solvent used is 2-2.5 mL / mmol (preferably 2.5 mL / mmol) based on the molar amount of compound C.

[0023] Further, in step (3), the molar ratio of glyoxal to formaldehyde is 1:1-5 (preferably 1:4); the molar ratio of glyoxal to compound D and ammonium acetate is 1:1-3 (preferably 1:1); the total volume of methanol used is 2-2.5 mL / mmol (preferably 2 mL / mmol) based on the molar amount of glyoxal; the glyoxal is added in the form of a 40% aqueous solution, and the formaldehyde is added in the form of a 37% aqueous solution; the volume ratio of methanol added to the reaction flask to that added to the beaker is 1:2.

[0024] Furthermore, in step (4), the molar ratio of compound F to compound E is 1:1-5 (preferably 1:4); the volume of m-xylene used is 1.5-2 mL / mmol (preferably 2 mL / mmol) based on the molar amount of compound F.

[0025] Thirdly, the present invention provides the application of the chiral α-amino acid in the synthesis of chiral phosphoramide compounds.

[0026] Further, the application method is as follows: compound J is added to a reaction tube, followed by the chiral α-amino acid as a catalyst, and then toluene is added to dissolve it. The reaction tube is placed in a -20°C low-temperature reactor and stirred for 20 minutes. Compound K (2-(methylsulfonyl)phenol sodium) is added, and the reaction is continued to be stirred for 48 hours. Using dichloromethane / methanol at a volume ratio of 50:1 as the eluent, the mixture is eluted under pressure. The effluent is subjected to thin-layer chromatography monitoring using dichloromethane / methanol at a volume ratio of 30:1 as the developing solvent. The fraction with an Rf value of 0.4-0.6 is collected, and the solvent is removed by rotary evaporation under reduced pressure to obtain a white solid, which is the chiral phosphoramide compound L.

[0027]

[0028] R in compound K 2 Hydrogen, chlorine, methyl; R in chiral phosphoramide compounds L 2 In the same compound K, R 2 .

[0029] Furthermore, the amount of the chiral α-amino acid feed is 0.002% of the amount of compound K feed; the ratio of the amounts of compound K and compound J feed is 1:0.5-1 (preferably 1:0.6); and the volume of toluene used is 5-20 mL / mmol based on the amount of compound K.

[0030] Compared with the prior art, the beneficial effects of the present invention are mainly reflected in:

[0031] The chiral α-amino acid with a C3 symmetric structure provided by this invention is more structurally stable than some other ion-pair catalysts due to its C3 symmetric structure. It can also successfully construct chiral phosphoramide compounds with high yield (70%-80%) and enantioselectivity (80%-95%), thus exhibiting superior catalytic performance and solving the problem of traditional ion-pair catalysts being difficult to construct chiral phosphoramide compounds. (iv) Description of the attached drawings

[0032] Figure 1 These are the NMR spectra of the chiral α-amino acids prepared in Examples 1-8, where AH represents the proton NMR spectrum and ah represents the carbon NMR spectrum.

[0033] Figure 2 This is the NMR spectrum of product L-1, where A represents H NMR, B represents C NMR, and C represents P NMR.

[0034] Figure 3are the nuclear magnetic spectra of product L-2, A represents H NMR, B represents C NMR, and C represents P NMR.

[0035] Figure 4 are the nuclear magnetic spectra of product L-3, A represents H NMR, B represents C NMR, and C represents P NMR.

[0036] Figure 5 is the high performance liquid chromatogram of product L-1, A represents racemic substrate, and B represents product.

[0037] Figure 6 is the high performance liquid chromatogram of product L-2, A represents racemic substrate, and B represents product.

[0038] Figure 7 is the high performance liquid chromatogram of product L-3, A represents racemic substrate, and B represents product. (V) SPECIFIC EMBODIMENT

[0039] The application will be further described in conjunction with specific examples, but the protection scope of the application is not limited to the following:

[0040] In the embodiment of the application, the silica gel column chromatography adopts 2x30cm Xinhui glass column; and commercially available 300-400 mesh silica gel powder is used.

[0041] Example 1, preparation of chiral α-amino acid I-1

[0042]

[0043] (1) 25 mL of dichloromethane solvent (DCM) was added to a reaction bottle, and then compound B (BOC-L-leucine, 2.4153 g, 10.5 mmol, 1.05 equiv.), compound A (1.7239 mL, 10.0 mmol, 1.0 equiv.), 1-hydroxybenzotriazole (HOBt, 2.0250 g, 15.0 mmol, 1.5 equiv.), N, N-diisopropyl ethylamine (DIPEA, 2.6078 mL, 15.0 mmol, 1.5 equiv.), 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride (2.8755 mg, 15.0 mmol, 1.5 equiv.) were added in sequence, and stirred at room temperature for 12 h. After removing the solvent by rotary evaporation under reduced pressure, silica gel column chromatography was performed, and the eluent was dichloromethane / methanol (30:1, by volume) under pressure. The effluent was monitored by thin layer chromatography with dichloromethane / methanol (30:1, by volume) as developing agent. The components with Rf value of 0.7-0.8 were collected, and the solvent was removed by rotary evaporation under reduced pressure to obtain 3.2888 g of light yellow liquid, which was compound C, and the mass yield was 83%.

[0044] (2) Put compound C (3.1699 g, 8.0 mmol, 1.0 equiv.) into a reaction bottle, dissolve in 20 mL of dichloromethane solvent, slowly drop trifluoroacetic acid (TFA, 3.5648 ml, 48 mmol, 6.0 equiv.), stir at room temperature for 12 h; after the end of stirring, extract with saturated NaHCO3 aqueous solution and dichloromethane respectively for three times, take the organic phase, remove the solvent by rotary evaporation under reduced pressure, then perform silica gel column chromatography, use dichloromethane / methanol (50:1 by volume ratio) as eluent, pressurized elution, monitor the flow-out liquid by thin layer chromatography using dichloromethane / methanol (10:1 by volume ratio) as developing agent, collect the components with Rf value of 0.4-0.5, remove the solvent by rotary evaporation under reduced pressure to obtain 2.0378 g of light yellow liquid, which is compound D, the mass yield is 86%;

[0045] (3) Put 40% glyoxal aqueous solution (0.8061 mL, 7.0 mmol, 1.0 equiv.) and 37% formaldehyde aqueous solution (2.1042 mL, 28.0 mmol, 4.0 equiv.) in a reaction bottle, add 5 mL of methanol; then take another beaker, add compound D (2.0733 g, 7.0 mmol, 1.0 equiv.) and ammonium acetate (0.5396 g, 7.0 mmol, 1.0 equiv.), dissolve in 10 mL of methanol, slowly drop into the above reaction bottle, after the end of dropping, stir at room temperature for 12 h. Remove the solvent by rotary evaporation under reduced pressure, add dichloromethane and anhydrous sodium sulfate to remove water, filter, remove the solvent by rotary evaporation under reduced pressure, then perform silica gel column chromatography, use dichloromethane / methanol (50:1 by volume ratio) as eluent, pressurized elution, monitor the flow-out liquid by thin layer chromatography using dichloromethane / methanol (20:1 by volume ratio) as developing agent, collect the components with Rf value of 0.4-0.6, obtain 1.4825 g of light yellow liquid, which is compound E, the mass yield is 61%;

[0046] (4) Put compound E (1.3938 g, 4.0 mmol, 4.0 equiv.) into a reaction bottle, add compound F (methylbenzene, 0.3568 g, 1.0 mmol, 1.0 equiv.), then add 8 mL of m-xylene to dissolve, stir at 150°C for 24 h, after the end of reaction, remove the solvent by rotary evaporation under reduced pressure, then perform silica gel column chromatography, use dichloromethane / methanol (15:1 by volume ratio) as eluent, pressurized elution, monitor the flow-out liquid by thin layer chromatography using dichloromethane / methanol (10:1 by volume ratio) as developing agent, collect the components with Rf value of 0.3-0.4, concentrate to dryness under reduced pressure, obtain 0.5214 g of white solid, which is compound I-1, the mass yield is 45%, the hydrogen spectrum is shown in Figure 1 Figure 1 ​as shown in a.

[0047] 3,3',3"-(benzene-1,3,5-triyltris(methylene))tris(1-((S)-1-(benzhydrylamino)-4-methyl-1-oxopentan-2-yl)-1H-imidazol-3-ium tribromide)(I-1)

[0048]

[0049] The product was a white solid, yield: 45%; 1 H NMR (500 MHz, DMSO-d6) δ 9.73 - 9.48 (m, 6H), 7.92 (s, 3H), 7.81 (s, 3H), 7.41 - 7.22 (m, 33H), 6.07 (d, J = 8.0 Hz, 3H), 5.50 - 5.39 (m, 6H), 4.48 (t, J = 4.6 Hz, 3H), 2.53 - 2.49 (m, 9H), 2.10 - 1.93 (m, 6H), 1.30 - 1.21 (m, 3H), 0.93 - 0.83 (m, 18H); 13 C NMR (126 MHz, DMSO-d6) δ 170.81, 167.22, 142.17, 141.90, 137.04, 136.72, 129.26, 129.02, 128.90, 127.78, 127.74, 127.60, 123.19, 122.56, 60.93, 60.22, 57.35, 52.00, 24.84, 22.87. HRMS (ESI) m / z calculated for C 75 H 84 N9O3 3+ [M-Br] + : 386.2227, found: 386.2238.

[0050] Example 2-8

[0051] Using the method of Example 1, the compound B in which R 1 is replaced by neopentyl, phenethyl, isopropyl, methyl, propyl, n-butyl, 2-methylthiomethyl, respectively, to obtain compounds I-2~I-8, the nuclear magnetic hydrogen spectrum and carbon spectrum are shown in Figure 1 , the structure and nuclear magnetic data are as follows:

[0052] 3,3',3"-(benzene-1,3,5-triyltris(methylene))tris(1-((S)-1-(benzhydrylamino)-4,4-dimethyl-1-oxopentan-2-yl)-1H-imidazol-3-ium tribromide) (I-2)

[0053]

[0054] The product was a white solid, yield: 47%; 1 H NMR δ 9.73 (s, 3H), 9.68 (d, J = 8.2 Hz, 3H), 7.96 (s, 3H), 7.80 (s, 3H), 7.52 (s, 3H), 7.41 - 7.19 (m, 33H), 6.07 (d, J = 8.2 Hz, 3H), 5.59 - 5.53 (m, 3H), 5.51 - 5.33 (m, 6H), 2.12 - 1.98 (m, 6H), 0.78 (s, 27H); 13 C NMR (126 MHz, DMSO-d6) δ 167.4, 141.9, 136.9, 136.7, 129.4, 129.0, 128.9, 127.8, 127.6, 127.6, 123.2, 122.5, 60.1, 57.4, 52.0, 44.7, 30.9, 29.5; HRMS (ESI) m / z calculated for C 78 H 90 N9O3 3+ [M-Br] + : 400.2384, found: 400.2391.

[0055] 3,3',3"-(benzene-1,3,5-triyltris(methylene))tris(1-((S)-1-(benzhydrylamino)-1-oxo-4-phenylbutan-2-yl)-1H-imidazol-3-ium tribromide) (I-3)

[0056]

[0057] The product was a white solid, yield: 43%; 1H NMR δ 9.64 (s, 3H), 9.62 (d, J = 8.3 Hz, 3H), 7.84 - 7.79 (m, 6H), 7.59 (s, 3H), 7.41 - 7.07 (m, 45H), 6.10 (d, J = 8.1 Hz, 3H), 5.46 (d, J = 5.1 Hz, 6H), 5.44 - 5.39 (m, 3H), 2.67 - 2.31 (m, 12H); 13 C NMR (126 MHz, DMSO-d6) δ 166.8, 142.2, 141.8, 140.3, 137.2, 136.7, 129.4, 129.0, 128.9, 128.9, 128.7, 127.8, 127.7, 126.7, 123.2, 122.5, 62.5, 57.4, 52.0, 34.0, 31.8; HRMS (ESI) m / z calculated for C 87 H 84 N9O3 3+ [M-Br] + : 434.2227, found: 434.2235.

[0058] 3,3',3"-(benzene-1,3,5-triyltris(methylene))tris(1-((S)-1-(benzhydrylamino)-3-methyl-1-oxobutan-2-yl)-1H-imidazol-3-ium tribromide) (I-4)

[0059]

[0060] The product was a white solid in 40% yield; 1 H NMR (500 MHz, DMSO-d6) δ 9.70 (d, J = 8.3 Hz, 3H), 9.62 (s, 3H), 7.88 (s, 3H), 7.81 (s, 3H), 7.53 (s, 3H), 7.40 - 7.19 (m, 33H), 6.12 (d, J = 8.3 Hz, 3H), 5.53 - 5.43 (m, 6H), 5.14 (d, J = 8.8 Hz, 3H), 2.45 (dp, J = 8.7, 6.7 Hz, 3H), 0.88 (d, J = 6.7 Hz, 9H), 0.73 (d, J = 6.7 Hz, 9H); 13C NMR (126 MHz, DMSO-d6) δ 166.5, 142.2, 141.8, 136.8, 136.8, 129.3, 129.0, 128.9, 127.8, 127.7, 127.7, 127.6, 123.4, 122.5, 67.8, 57.3, 52.0, 31.8, 19.0, 18.5; HRMS (ESI) m / z calculated for C 70 H 72 N9O3 3+ [M-Br] + : 372.2071, found: 372.2078.

[0061] 3,3',3"-(benzene-1,3,5-triyltris(methylene))tris(1-((S)-1-(benzhydrylamino)-1-oxopropan-2-yl)-1H-imidazol-3-ium tribromide) (I-5)

[0062]

[0063] The product was a white solid in 41% yield; 1 H NMR (500 MHz, DMSO-d6) δ 9.59 (s, 3H), 9.51 (d, J = 8.2 Hz, 3H), 7.85 (s, 3H), 7.80 (s, 3H), 7.52 (s, 3H), 7.40 - 7.22 (m, 33H), 6.08 (d, J = 8.2 Hz, 3H), 5.45 (d, J = 11.6 Hz, 9H), 1.76 (d, J = 7.2 Hz, 9H); 13 C NMR (126 MHz, DMSO-d6) δ 167.8, 142.3, 142.0, 137.0, 136.8, 129.0, 128.9, 127.9, 127.7, 127.7, 127.5, 123.2, 122.4, 58.1, 57.3, 51.9, 18.8; HRMS (ESI) m / z calculated for C 66 H 66 N9O3 3+ [M-Br] + : 344.1758, found: 344.1768.

[0064] 3,3',3"-(benzene-1,3,5-triyltris(methylene))tris(1-((S)-1-(benzhydrylamino)-1-oxopentan-2-yl)-1H-imidazol-3-ium tribromide) (I-6)

[0065]

[0066] The product was a white solid in 43% yield; 1 H NMR (500 MHz, DMSO-d6) δ 9.64 - 9.57 (m, 6H), 7.87 (s, 3H), 7.81 (s, 3H), 7.53 (s, 3H), 7.41 - 7.20 (m, 33H), 6.09 (d, J = 8.1 Hz, 3H), 5.52 - 5.43 (m, 6H), 5.42 - 5.36 (m, 3H), 2.20 - 2.10 (m, 3H), 2.08 - 1.99 (m, 4H), 1.24 - 1.10 (m, 6H), 0.87 (t, J = 7.3 Hz, 9H); 13 C NMR (126 MHz, DMSO-d6) δ 167.1, 142.3, 141.9, 137.0, 136.7, 129.2, 129.0, 128.9, 127.8, 127.7, 127.6, 123.2, 122.5, 62.2, 57.3, 52.0, 34.3, 18.9, 13.6; HRMS (ESI) m / z calcd for C 72 H 78 N9O3 3+ [M-Br] + : 372.2071, found: 372.2075.

[0067] 3,3',3"-(benzene-1,3,5-triyltris(methylene))tris(1-((S)-1-(benzhydrylamino)-1-oxohexan-2-yl)-1H-imidazol-3-ium tribromide) (I-7)

[0068]

[0069] The product was a white solid in 43% yield; 1H NMR (500 MHz, DMSO-d6) δ 9.65 - 9.60 (m, 6 H), 7.86 (s, 3 H), 7.82 (s, 3 H), 7.54 (s, 3 H), 7.45 - 7.16 (m, 33 H), 6.09 (d, J = 8.2 Hz, 3 H), 5.51 - 5.42 (m, 6 H), 5.38 (dd, J = 9.1, 6.1 Hz, 3 H), 2.23 - 2.13 (m, 3 H), 2.08 - 1.99 (m, 3 H), 1.31 - 1.24 (m, 6 H), 1.19 - 1.06 (m, 6 H), 0.81 (t, J = 7.3 Hz, 9 H); 13 C NMR (126 MHz, DMSO-d6) δ 167.1, 142.3, 141.9, 137.0, 136.7, 129.3, 129.0, 128.9, 127.8, 127.7, 127.7, 127.6, 123.2, 122.6, 62.4, 57.3, 52.0, 32.3, 27.7, 21.9, 14.2; HRMS (ESI) m / z calcd for C 75 H 84 N9O3 3+ [M-Br] + : 386.2227, found: 386.2238.

[0070] 3,3',3"-(benzene-1,3,5-triyltris(methylene))tris(1-((R)-1-(benzhydrylamino)-3-(methylthio)-1-oxopropan-2-yl)-1H-imidazol-3-iumtribromide) (I-8)

[0071]

[0072] The product was a white solid in 44% yield; 1 H NMR (500 MHz, DMSO-d6) δ 9.69 (d, J = 8.1 Hz, 3 H), 9.66 (s, 3 H), 7.93 (s, 3 H), 7.80 (s, 3 H), 7.49 (s, 3 H), 7.41 - 7.22 (m, 33 H), 6.10 (d, J = 8.0 Hz, 3 H), 5.61 (dd, J = 10.4, 5.2 Hz, 3 H), 5.55 - 5.43 (m, 6 H), 3.39 (dd, J = 14.3, 5.1 Hz, 3 H), 3.22 (dd, J = 14.2, 10.5 Hz, 3 H), 2.07 (s, 9 H); 13C NMR (126 MHz, DMSO-d6) δ 165.8, 142.0, 141.8, 137.4, 136.7, 129.1, 129.0, 129.0, 127.9, 127.8, 127.7, 127.6, 123.5, 122.5, 61.1, 57.5, 52.0, 35.8, 14.9; HRMS (ESI) m / z calcd for C 69 H 72 N9O3S3 3+ [M-Br] + : 390.1635, found: 390.1640.

[0073] Example 9, Application of Compound I

[0074] 1. Comparison of Compound I-1 and other ions for catalyst synthesis of chiral phosphoramidate

[0075] Substrate compound J (N-(mesitylenesulfonyloxy)-P,P-diphenyl phosphoramidite, 0.0311 g, 0.075 mmol, 1.5 equiv.) was added to the reaction tube, followed by the catalyst (0.0012 g, 0.02 equiv.) including compound I-1 in Table 1, which was dissolved in 1 mL of toluene, and the reaction tube was placed in a -20 °C low-temperature reactor for stirring for 20 min, followed by the addition of compound K-1 (0.0097 g, 0.05 mmol, 1 equiv.), and the reaction was continued for 48 h with stirring, elution was performed with dichloromethane / methanol (50:1 by volume) under pressure, and the effluent was monitored by thin-layer chromatography with dichloromethane / methanol (30:1 by volume) as the developing agent, the components with an Rf value of 0.4-0.6 were collected, and the sample was detected by HPLC to calculate the ee value, and the remaining components were subjected to rotary evaporation under reduced pressure to remove the solvent to obtain white solid, which was weighed to calculate the yield, and the results are shown in Table 1.

[0076] HPLC detection conditions: ND Chiral column, n-hexane / isopropanol = 70 / 30, 1.0 mL / min, 254 nm, 25 °C

[0077]

[0078] Table 1, Comparison of different catalysts for the synthesis of chiral phosphoramidate

[0079]

[0080]

[0081] 2. Synthesis of different chiral phosphoramidate compounds catalyzed by compound I-1

[0082] The substrate compound K in Step 1 was replaced by 2-(methylsulfonyl)phenyl sodium, 4-chloro-2-(methylsulfonyl)phenyl sodium, 4-methyl-2-(methylsulfonyl)phenyl sodium, and other operations were the same, to obtain products L-1, L-2 and L-3, respectively. The H NMR, C NMR, and P NMR spectra are shown in Figure 2 、 3 , A, B, and C shown in FIG. 4; and the high performance liquid chromatogram is shown in Figure 5 、 6 , 7.

[0083]

[0084] 2-(methylsulfonyl)phenyl N,P-diphenylphosphonamidate (L-1)

[0085] The product was a white solid; 1 H NMR (500 MHz, CDCl3) δ 8.15-8.08 (m, 2H), 8.08-8.03 (m, 1H), 7.95-7.90 (m, 1H), 7.74-7.64 (m, 1H), 7.64-7.58 (m, 1H), 7.56-7.50 (m, 2H), 7.43-7.36 (m, 1H), 7.19-7.12 (m, 2H), 7.12-7.03 (m, 2H), 6.95-6.87 (m, 1H), 6.85 (d, J = 7.2 Hz, 1H), 3.17 (s, 3H); 13 C NMR (126 MHz, CDCl3) δ 148.7 (d, J = 8.6 Hz), 139.4, 136.2, 133.0, 131.9 (d, J = 11.0 Hz), 131.0 (d, J = 5.1 Hz), 130.0, 129.8, 129.2, 128.8 (d, J = 15.5 Hz), 125.5, 123.6, 122.3, 118.5 (d, J = 6.5 Hz), 43.3; 31 PNMR (202 MHz, CDCl3) δ 16.79. HRMS (ESI) m / z calculated for C 19 H 18 NO4PS + [M+Na] + : 410.0592, found: 410.0584.

[0086] 4-chloro-2-(methylsulfonyl)phenyl N,P-diphenylphosphonamidate (L-2)

[0087] The product was a white solid; 1 H NMR (500 MHz, CDC13) δ 8.13 - 8.05 (m, 2 H), 8.05 - 8.01 (m, 1 H), 7.92 - 7.86 (m, 1 H), 7.65 - 7.59 (m, 2 H), 7.57 - 7.52 (m, 2 H), 7.20 - 7.13 (m, 2 H), 7.11 - 7.06 (m, 2 H), 6.96 - 6.89 (m, 1 H), 6.72 (d, J = 7.4 Hz, 1 H), 3.17 (s, 3 H); 13 C NMR (126 MHz, CDC13) δ 147.2 (d, J = 8.1 Hz), 139.2, 135.9, 133.2 (d, J = 2.6 Hz), 132.3, 131.9 (d, J = 11.0 Hz), 131.2, 129.6, 129.3, 128.9 (d, J = 15.5 Hz), 124.9, 122.5, 118.5 (d, J = 6.5 Hz), 43.2; 31 P NMR (202 MHz, CDC13) δ 17.37. HRMS (ESI) m / z calculated for C 19 H 17 ClNO4PS + [M+Na] + : 444.0202, found: 444.0197.

[0088] 4-methyl-2-(methylsulfonyl)phenyl N,P-diphenylphosphonamidate (L-3)

[0089] The product was a white solid; 1 H NMR (500 MHz, CDC13) δ 8.13 - 8.05 (m, 2 H), 8.05 - 8.01 (m, 1 H), 7.92 - 7.86 (m, 1 H), 7.65 - 7.59 (m, 2 H), 7.57 - 7.52 (m, 2 H), 7.20 - 7.13 (m, 2 H), 7.11 - 7.06 (m, 2 H), 6.96 - 6.89 (m, 1 H), 6.72 (d, J = 7.4 Hz, 1 H), 3.17 (s, 3 H); 13C NMR (126 MHz, CDC13) δ 146.3 (d, J = 8.4 Hz), 139.5, 136.6, 135.8, 132.9, 131.9 (d, J = 11.0 Hz), 130.4 (d, J = 3.9 Hz), 129.8, 129.2, 128.8 (d, J = 15.5 Hz), 123.4, 122.1, 118.4 (d, J = 6.5 Hz), 43.3, 20.7; 31 PNMR (202 MHz, CDC13) δ 16.59. HRMS (ESI) m / z calculated for C 20 H 20 NO4PS + [M+Na] + : 424.0748, found: 424.0740.

[0090] The above examples describe the basic principles, main features and advantages of the present application, those skilled in the art should understand that the present application should not be limited by the above examples, the above examples and the content described in the specification are only to illustrate the principles of the present application, without departing from the scope of the principles of the present application, the present application can also have various optimizations and improvements, and these optimizations and improvements all fall within the scope of the present application.

Claims

1. A chiral α-amino acid having a C3 symmetry structure as shown in formula I: ###0001### Formula I In formula I, R 1 each independently isobutyl, neopentyl, phenethyl, isopropyl, methyl, propyl, n-butyl, 2-methylthiomethyl.

2. The chiral α-amino acid according to claim 1, wherein The chiral α-amino acid having a C3 symmetry structure as shown in formula I is one of the following:

3. A process for the preparation of a chiral α-amino acid according to claim 1, characterized in that The method comprises the following steps: (1) adding dichloromethane into a reaction bottle, then adding compound B, compound A, 1-hydroxybenzotriazole, N,N-diisopropylethylamine and 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride in sequence, stirring at room temperature for 12 h, removing the solvent by rotary evaporation under reduced pressure, and then performing silica gel column chromatography, eluting under pressure with dichloromethane / methanol (30:1 by volume ratio) as the eluent, monitoring the effluent with thin layer chromatography using dichloromethane / methanol (30:1 by volume ratio) as the developing agent, collecting the components with Rf value of 0.7-0.8, and removing the solvent by rotary evaporation under reduced pressure to obtain a light yellow liquid, which is compound C; (2) adding compound C into a reaction bottle, dissolving in dichloromethane, slowly dropping trifluoroacetic acid, stirring at room temperature for 12 h, respectively extracting three times with saturated NaHCO3 aqueous solution and dichloromethane, taking the organic phase, removing the solvent by rotary evaporation under reduced pressure, and then performing silica gel column chromatography, eluting under pressure with dichloromethane / methanol (50:1 by volume ratio) as the eluent, monitoring the effluent with thin layer chromatography using dichloromethane / methanol (10:1 by volume ratio) as the developing agent, collecting the components with Rf value of 0.4-0.5, and removing the solvent by rotary evaporation under reduced pressure to obtain a light yellow liquid, which is compound D; (3) adding a 40% (by volume) aqueous glyoxal solution and a 37% (by volume) aqueous formaldehyde solution into a reaction bottle, and adding methanol; then adding compound D and ammonium acetate into another beaker, dissolving in methanol, and slowly dropping into the above reaction bottle, stirring at room temperature for 12 h after dropping is completed, removing the solvent by rotary evaporation under reduced pressure, adding dichloromethane and anhydrous sodium sulfate to remove water, filtering, removing the solvent by rotary evaporation under reduced pressure, and then performing silica gel column chromatography, eluting under pressure with dichloromethane / methanol (50:1 by volume ratio) as the eluent, monitoring the effluent with thin layer chromatography using dichloromethane / methanol (20:1 by volume ratio) as the developing agent, collecting the components with Rf value of 0.4-0.6, and removing the solvent by rotary evaporation under reduced pressure to obtain a light yellow liquid, which is compound E; (4) adding compound E into a reaction bottle, adding compound F, and then adding m-xylene to dissolve, stirring at 150°C for 24 h, removing the solvent by rotary evaporation under reduced pressure after reaction is completed, performing silica gel column chromatography, eluting under pressure with dichloromethane / methanol (15:1 by volume ratio) as the eluent, monitoring the effluent with thin layer chromatography using dichloromethane / methanol (10:1 by volume ratio) as the developing agent, collecting the components with Rf value of 0.3-0.4, concentrating to dryness under reduced pressure, and removing the solvent by rotary evaporation under reduced pressure to obtain white solid, which is the chiral α-amino acid as shown in formula I; R in compound B 1 The compounds are isobutyl, neopentyl, phenethyl, isopropyl, methyl, propyl, n-butyl, and 2-methylthiomethyl; R in compounds C, D, E, and I. 1 In compound B, R 1 .

4. The production method according to claim 3, wherein The molar ratio of compound A to compound B in step (1) is 1:1-2; the molar ratio of compound A to 1-hydroxybenzotriazole, N, N-diisopropylethylamine, 1-ethyl-(3-dimethylaminopropyl) carbodiimide hydrochloride is 1:1-2; the volume of solvent dichloromethane is 2-2.5 mL / mmol based on the molar amount of compound A.

5. The production method according to claim 3, wherein The molar ratio of compound C to trifluoroacetic acid in step (2) is 1:5-10; the volume of solvent dichloromethane is 2-2.5 mL / mmol based on the molar amount of compound C.

6. The production method according to claim 3, wherein The molar ratio of glyoxal to formaldehyde in step (3) is 1:1-5; the molar ratio of glyoxal to compound D, ammonium acetate is 1:1-3; the total volume of methanol is 2-2.5 mL / mmol based on the molar amount of glyoxal; the glyoxal is added in the form of a 40% aqueous solution by volume concentration, and the formaldehyde is added in the form of a 37% aqueous solution by volume concentration.

7. The production method according to claim 3, wherein The molar ratio of compound F to compound E in step (4) is 1:1-5; the volume of m-xylene is 1.5-2 mL / mmol based on the molar amount of compound F.

8. Use of the chiral α-amino acid of claim 1 in the synthesis of a chiral phosphoramidate compound.

9. Use according to claim 8, wherein the compound is ###0002### The method of the use is: adding compound J into a reaction test tube, then adding the chiral α-amino acid as a catalyst, and then adding toluene for dissolution, placing the reaction test tube in a -20℃ low-temperature reactor for stirring for 20 minutes, adding compound K, continuing to stir for reaction for 48 h, using dichloromethane / methanol with a volume ratio of 50:1 as an eluent for pressure elution, using dichloromethane / methanol with a volume ratio of 30:1 as a developing agent for monitoring by thin-layer chromatography, collecting components with an Rf value of 0.4-0.6, and removing the solvent by rotary evaporation under reduced pressure to obtain a white solid, which is the chiral phosphoramidate compound L. R in compound K 2 is hydrogen, chlorine, methyl; R in chiral phosphoramidite compound L 2 same as R in substrate K 2 .

10. Use according to claim 9, wherein the compound is ###00010### or a pharmaceutically acceptable salt thereof. The amount of the chiral α-amino acid is 0.002% of the amount of the amount of compound K; the ratio of the amount of compound K to the amount of compound J is 1:0.5-1; and the volume of toluene is 5-20 mL / mmol based on the amount of compound K.

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