Phosphamide compound with pentavalent phosphorus chiral center and one-pot synthesis method thereof

Abstract

The invention relates to the technical field of chemical raw material medicine manufacturing, in particular to a phosphonamide compound with a pentavalent phosphorus chiral center and a one-pot synthesis method of the phosphonamide compound. The structural formula of the compound is shown as (V). The synthesis method comprises the following steps: by taking chiral bicyclic imidazole as a catalyst, carrying out enantioselective amino substitution reaction on a phosphonic dichloride raw material (I) and a secondary amine reactant (II) to obtain a chiral aminophosphoryl chloride intermediate (III), and carrying out stereospecific nucleophilic substitution on the chiral aminophosphoryl chloride intermediate (III) and a nucleophilic reagent (IV) to obtain a chiral phosphoramide product (V). By adopting the method, the substrate adaptability is wide, the enantioselectivity is excellent, the product derivatization is strong, and a universal platform is provided for efficient synthesis of phosphorus chiral bioactive molecules.

Description

Technical Field

[0001] This invention relates to the field of chemical pharmaceutical raw material manufacturing technology, specifically to phosphonamide compounds having a pentavalent phosphorus chiral center and their one-pot synthesis method. Background Technology

[0002] Chiral pentavalent phosphonooxides are an important class of molecules, serving as key pharmacophores or structural skeletons and showing broad application prospects in medicinal chemistry and catalysis. These structures are found in a variety of bioactive molecules and marketed drugs. Typical examples include the antiviral drug tenofovir alafenamide (Biochemical Pharmacology 2016, 119, 1–7), the Utrophin modulator SMT022332 used to treat Duchenne muscular dystrophy, and the hypotensive drug fosinopril based on a hypophosphonic acid structure (International Microbiology 2025, 28, 1197–1209). Therefore, developing efficient synthetic methods for these chiral molecules is of great significance for drug development and related disciplines.

[0003] Currently, traditional methods for constructing P(V)-chiral centers mainly rely on chiral resolution of racemates or chiral auxiliary group-induced synthesis. The former has inherent limitations, with a theoretical yield not exceeding 50%, and inevitably produces ineffective enantiomers; the latter requires the use of stoichiometric chiral reagents and involves the introduction and removal of auxiliary groups, resulting in lengthy synthetic steps, low atom economy, and high costs. These inherent defects severely limit the widespread application of this class of chiral phosphine compounds.

[0004] Therefore, developing an efficient, highly selective, and atom-economical catalytic asymmetric synthesis method is of great research significance and application value for the preparation of this type of chiral phosphine oxide. Summary of the Invention

[0005] The purpose of this invention is to provide phosphonamide compounds with pentavalent phosphorus chiral centers and a one-pot synthesis method thereof to solve the problems.

[0006] To achieve the above objectives, the present invention adopts the following technical solution: This invention provides a synthetic route for constructing chiral pentavalent phosphine oxides (V) via a one-pot method, as shown below:

[0007] A diverse range of compounds with pentavalent phosphorus chiral centers were efficiently constructed in a one-pot process via enantioselective amino substitution followed by stereospecific nucleophilic substitution. Under an inert atmosphere, using chiral bicyclic imidazole as a catalyst and activated molecular sieves as a dehydrating agent, phosphonyl dichloride (I) and secondary amine (II) reacted at low temperature in an organic solvent. Then, a nucleophile (IV) and additives were added, and the reaction continued. Subsequent post-treatment yielded the chiral phosphonamide product (V).

[0008] Furthermore, the chiral configuration of phosphorus is... R or S R is a C7-C8 alkyl or C6-C13 aryl, wherein the C6-C13 aryl is substituted by one or two C1-C7 hydrocarbon groups; and the C6-C13 aryl or the hydrocarbon-substituted C6-C13 aryl may optionally be further substituted on its aromatic ring by one or more substituents independently selected from halogen, alkoxy, trifluoromethyl, phenyl or phenoxy. 1 and R 2 The group is either an alkyl or an aryl substituent, and the two can be the same or different.

[0009] Furthermore, in the secondary amine raw material (II), R 1 and R 2 The group is any one of ethyl, n-propyl, isopropyl, n-butyl, isobutyl, benzyl, phenyl, or substituted phenyl, R 1 and R 2 The functional groups can be the same or different.

[0010] Furthermore, the structural formula of the chiral bicyclic imidazole catalyst is as follows: , The chiral configuration of the carbon atom marked with an asterisk (*) is: R or S Ar represents aryl.

[0011] Further, the organic solvent is one or two ether solvents, such as diethyl ether, methyl tert-butyl ether, isopropyl ether, tetrahydrofuran, 1,4-dioxane, ethylene glycol dimethyl ether, ethylene glycol monomethyl ether, propylene glycol dimethyl ether, or methoxycyclopentyl ether; preferably ethylene glycol dimethyl ether and methoxycyclopentyl ether; the volume ratio of the ethylene glycol dimethyl ether to the methoxycyclopentyl ether can be 1 / (1~2), preferably 1 / 1.5.

[0012] Furthermore, the molar ratio of the phosphonyl dichloride raw material (Ⅰ) to the secondary amine raw material (Ⅱ) is 1 / (2~4), preferably 1 / 3.5.

[0013] Furthermore, the molar ratio of the phosphonyl dichloride raw material (Ⅰ) to the chiral bicyclic imidazole catalyst is 1 / (0.05~0.30), preferably 1 / 0.15.

[0014] Furthermore, the temperature of the low-temperature reaction is (-80℃) to (-20℃), preferably -50℃.

[0015] Furthermore, the low-temperature reaction time is 12h to 60h, preferably 36h.

[0016] Furthermore, adding an active molecular sieve during the low-temperature reaction can improve the yield, preferably a 4Å molecular sieve.

[0017] Furthermore, the nucleophile NuH can be an alcohol, thiol, phenol, thiophenol, primary amine, secondary amine, Grignard reagent, or its sodium salt form NuNa.

[0018] Furthermore, the reaction temperature for stereospecific nucleophilic substitution is (-80℃) to (30℃), preferably -50℃.

[0019] Furthermore, the additive is an inorganic salt, such as silver nitrate, silver carbonate, silver hexafluoroantimonate, potassium chloride, or sodium chloride, and its molar ratio with phosphonyl dichloride raw material (I) is (0.2~2.0) / 1, preferably 0.2 / 1.

[0020] Furthermore, the post-processing includes cold filtration, concentration, and plate boiling.

[0021] Furthermore, the reaction time for stereospecific nucleophilic substitution is 4 to 24 hours, preferably 12 hours.

[0022] Furthermore, the two-step reaction is carried out in a one-pot process without separating the intermediates.

[0023] A method for preparing a highly enantioselective chiral pentavalent phosphine compound (VI), the method comprising: subjecting a chiral phosphamide compound (V) to an alcoholysis reaction, breaking the PN bond and forming a PO bond, thereby obtaining the compound of formula (VI) with high enantioselectivity.

[0024]

[0025] Furthermore, compound (VI) undergoes a nucleophilic substitution reaction with an organolithium reagent, resulting in a rearrangement to form compound (VII) with a new PC(Ar) bond; compound (VI) reacts with Lawson's reagent to form compound (VIII) with a new P=S bond; compound (VI) reacts with Grignard reagent to form compound (IX) with a new PC bond; wherein, R 3The groups include alkyl and benzoynyl groups, where alkyl groups include one of methyl, ethyl, n-propyl, isopropyl, and n-butyl; R 4 Groups include electron-donating and electron-withdrawing groups. Electron-donating groups include one of methyl, ethyl, n-propyl, methoxy, and ethoxy groups, while electron-withdrawing groups include one of trifluoromethyl, nitro, and halogen groups; R 5 Groups include alkyl, alkoxy, allyl, and benzoynyl.

[0026] The objective of this invention is achieved through the following technical solution: (1) Enantioselective amino substitution reaction: Under an inert atmosphere, phosphonyl dichloride compound (Ⅰ), secondary amine compound (Ⅱ), chiral bicyclic imidazole catalyst and molecular sieve are added to an organic solvent and carried out an enantioselective nucleophilic substitution reaction at low temperature to generate intermediate (Ⅲ) with a phosphorus chiral center. (2) Stereospecific nucleophilic substitution reaction: Without separating intermediate (III), nucleophile (IV) and additive are added to the same reaction system, and the reaction is continued at a specific temperature to stereospecifically generate the target chiral phosphonamide product (V). (3) Post-processing: After the reaction is completed, the chiral phosphonamide product (V) with high optical purity is obtained by diatomaceous earth filtration, concentration and purification steps.

[0027] Compared with the prior art, the present invention has the following beneficial effects: The method of this invention is based on a synergistic catalytic mechanism, which realizes a highly efficient desymmetry reaction of phosphonyl dichloride. At the same time, the "one-pot" operation process avoids the separation of intermediates, simplifies the steps, and improves efficiency. The method of this invention has good substrate applicability. The PN bond in the obtained compound (V) can be broken by alcoholysis reaction, and further synthesize a variety of high-value chiral pentavalent phosphine functional molecules with chemical bonds such as PC and PS. Attached Figure Description

[0028] Figure 1 This is a synthetic route diagram of the phosphonamide compounds of the present invention. Detailed Implementation

[0029] The technical solution of the present invention will now be clearly and completely described with reference to the accompanying drawings in the embodiments of the present invention.

[0030] In the following embodiments of the present invention, the structural formula of the chiral bicyclic imidazole catalyst is shown below:

[0031] Example 1: ( R or S )- N,N -Diisobutyl- Pmethyl phenylphosphamide

[0032] Under inert gas protection, a 10 mL Slank tube was dried by heating with a hot air gun under reduced pressure and then cooled to room temperature; this drying process was repeated three times. Under inert gas protection, the following reagents were added sequentially to the tube: chiral bicyclic imidazole catalyst (0.03 mmol), 4 Å molecular sieve (70 mg), diisobutylamine (0.70 mmol, 3.50 equivalent), and anhydrous ethylene glycol dimethyl ether (1 mL). The reaction tube was sealed with a rubber stopper (reinforced with a Parafilm membrane) and purged with inert gas. The reaction mixture was cooled to -50 °C and stirred at this temperature for 20 minutes. Subsequently, a phosphonyl dichloride substrate solution (28 μL, 0.20 mmol, 1.0 equivalent) dissolved in anhydrous CPME (methylcyclopentyl ether, 1.5 mL) was added via syringe, and the reaction was continued to be stirred at -50 °C for 36 hours. A methanol solution of sodium methoxide (0.37 mL, 2.0 mmol, 5.4 mol / L [30 wt.%], sealed) was added directly to the aforementioned catalytic reaction system at -50 °C. After stirring at -50 °C for 12 hours, the reaction mixture was filtered through a diatomaceous earth filter to remove insoluble salts and molecular sieves. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography using silica gel.

[0033] Colorless oil (56 mg, 99% yield, 93% ee). 1 H NMR (400 MHz, CDCl3) δ 7.77 –7.72 (m, 2H), 7.51 – 7.40 (m, 3H), 3.72 (d, J =11.0 Hz, 3H), 2.89 – 2.74 (m,4H), 1.89 – 1.79 (m, 2H), 0.83 (d, J = 6.7 Hz, 6H), 0.78 (d, J = 6.6 Hz, 6H). 13 CNMR(101 MHz, CDCl3) δ 131.7 (d, J =9.1 Hz), 131.4 (d, J = 2.9 Hz), 131.2 (d, J =173.0 Hz), 128.3 (d, J =14.0 Hz), 52.9 (d, J = 3.8 Hz), 51.6 (d, J=5.7 Hz), 26.6(d, J = 2.7 Hz), 20.3 (d, J =19.3 Hz). 31 P NMR(162 MHz, CDCl3)δ 25.05.HRMS (ESI)m / zcalcd for C 15 H 27 NO2P(M+H) + :284.1779; found: 284.1776. Example 2: ( R or S )- N,N -Diisobutyl- P methyl phosphonamide (4-methoxyphenyl)

[0034] The experimental procedure is the same as in Example 1.

[0035] Colorless oil (62 mg, 99% yield, 95% ee). 1 H NMR (400 MHz, CDCl3) δ 7.67 (dd, J =8.8, 12 Hz, 2H), 6.94 (dd, J =8.8, 2.8 Hz, 2H), 3.84 (s, 3H), 3.69 (d, J = 10.8Hz, 3H), 2.87 – 2.71 (m, 4H), 1.87 – 1.82 (m, 2H), 0.83 (d, J = 6.6 Hz, 6H), 0.79 (d, J = 6.6 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 162.1 (d, J =3.2 Hz), 133.7 (d, J =10.3 Hz), 122.5 (d, J =180.4 Hz), 113.9 (d, J =15.1 Hz), 55.4, 53.1 (d, J =3.9Hz), 51.6 (d, J =5.8 Hz), 26.7 (d, J =2.8 Hz), 20.4 (d, J=15.4 Hz). 31 P NMR (162 MHz, CDCl3) δ 25.98.HRMS (ESI)m / z calcd for C 16 H 29 NO3P(M+H) + :314.1885; found:314.1884.HPLC conditions: CHIRALPAK OD-H, 3% iPrOH / hexanes, 0.8 mL / min, 220nm, t R (minor) = 12.685 min, t R (major) = 15.690 min. Example 3 ( R or S )- N,N -Diisobutyl- P methyl 4-(4-methylphenyl)phosphonamide

[0036] The experimental procedure is the same as in Example 1.

[0037] Colorless oil (53.3 mg, 90% yield, 85% ee). 1 H NMR (400 MHz, CDCl3) δ 7.66 –7.60 (m, 2H), 7.25 – 7.22 (m, 2H), 3.70 (d, J = 11.0 Hz, 3H), 2.87 – 2.75 (m,4H), 2.39 (s, 3H), 1.90 – 1.79 (m, 2H), 0.84 (d, J = 6.6 Hz, 6H), 0.79 (d, J =6.6 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 141.7 (d, J = 2.9 Hz), 131.8 (d, J = 9.4Hz), 129.1 (d, J = 14.5 Hz), 127.8 (d, J = 175.8 Hz), 53.0 (d, J = 4.0 Hz), 51.5(d, J = 5.5 Hz), 26.6 (d,J = 2.6 Hz), 21.7, 20.4 (d, J = 15.5 Hz). 31 P NMR(162MHz, CDCl3) δ 25.76.HRMS (ESI)m / z calcd for C 16 H 29 NO2P (M+H) + : 298.1936; found:298.1937.HPLC conditions: CHIRALPAK ODH, 3% iPrOH / hexanes, 0.8 mL / min, 220nm, t R (minor) = 8.664 min, t R (major) = 11.125 min. Example 4 ( R or S )- N,N -Diisobutyl- P methyl 4-phenylphenylphosphinoamide

[0038] The experimental procedure is the same as in Example 1.

[0039] Amorphous solids (58 mg, 81% yield, 84% ee). 1 H NMR (400 MHz, CDCl3) δ 7.81 (dd, J =12.1, 7.9 Hz, 2H), 7.66 (dd, J = 8.1, 3.5 Hz, 2H), 7.62 (d, J =8.1 Hz, 2H), 7.46(t, J =7.5 Hz, 2H), 7.41 – 7.26 (m, 1H), 3.74 (d, J =10.9 Hz, 3H), 2.96 – 2.78(m, 4H), 1.93 – 1.80 (m, 2H), 0.86 (d, J = 6.6 Hz, 6H), 0.81 (d, J = 6.6 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 144.1 (d, J = 3.1 Hz), 140.2, 132.3 (d,J = 9.4Hz), 130.7 (The signal for the carbon atom directly bonded to phosphorus wasobserved in the expected chemical shift range, with one leg of the characteristic doublet obscured by overlapping aromatic signals. All other spectroscopic data are in full agreement with the proposed structure), 129.0,128.1, 127.3, 127.0 (d, J = 14 Hz), 53.1 (d, J = 3.6 Hz), 51.6 (d, J = 5.8 Hz), 26.6 (d, J = 2.9 Hz), 20.4 (d, J = 16.0 Hz). 31 P NMR(162 MHz, CDCl3) δ 25.12.HRMS(ESI)m / z calcd forC 21 H 31 NO2P (M+H) + :360.2092; found:360.2098HPLC conditions:CHIRALPAK ODH, 3% iPrOH / hexanes, 0.8 mL / min, 220 nm, t R (minor) = 11.410 min,t R (major) = 15.147 min. Example 5 ( R or S )- N,N -Diisobutyl- P methyl phosphonamide (4-ethoxyphenyl)

[0040] The experimental procedure is the same as in Example 1.

[0041] Colorless oil (63 mg, 96% yield, 98% ee). 1H NMR(400 MHz, CDCl3)δ 7.83 – 7.61(m, 2H), 7.00 – 6.82 (m, 2H), 4.12 – 4.01 (m, 2H), 3.69 (d, J =11.0 Hz, 3H),2.87 – 2.72 (m, 4H), 1.87 – 1.80 (m, 2H), 1.43 (t, J = 7.0 Hz, 3H), 0.83 (d, J =6.6 Hz, 6H), 0.79 (d, J = 6.3 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 161.5 (d, J =3.3Hz), 133.7 (d, J =10.4 Hz), 122.2 (d, J =179.8 Hz), 114.3 (d, J = 15.0 Hz), 63.6,53.0 (d, J =3.9 Hz), 51.5 (d, J =5.7 Hz), 26.6 (d, J =2.7 Hz), 20.4 (d, J =16.0 Hz), 14.8. 31 P NMR(162 MHz, CDCl3) δ 26.09.HRMS (ESI)m / z calcd for C 17 H 31 NO3P(M+H) + :328.2042; found:328.2046.HPLC conditions: CHIRALPAK AD, 3% iPrOH / hexanes, 0.8mL / min, 220 nm, t R (minor) = 31.460 min, t R (major) = 34.274 min. Example 6 ( R or S )- N,N -Diisobutyl- P methyl phosphonamide (4-isopropoxyphenyl)

[0042] The experimental procedure is the same as in Example 1.

[0043] Colorless oil (65 mg, 95% yield, 98% ee). 1 H NMR (400 MHz, CDCl3) δ 7.64 (dd, J =11.9, 8.3 Hz, 2H), 6.91 (dd, J =8.8, 3.1 Hz, 2H), 4.66 – 4.57 (m, 1H), 3.69(d, J = 10.9 Hz, 3H), 2.87 – 2.72 (m, 4H), 1.89 – 1.79 (m, 2H), 1.35 (d, J =6.0Hz, 6H), 0.84 (d, J = 6.6 Hz, 6H), 0.79 (d, J = 6.6 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 160.4 (d, J =3.2 Hz), 133.6 (d, J = 10.3 Hz), 121.8 (d, J = 179.9 Hz), 115.3 (d, J = 14.9 Hz), 69.8, 53.0 (d, J =3.9 Hz), 51.4 (d, J = 5.6 Hz), 26.5 (d, J =2.7 Hz), 21.9 (d, J =2.6 Hz), 20.3 (d, J =16.2 Hz). 31 P NMR(162 MHz, CDCl3) δ26.16.HRMS (ESI)m / z calcd for C 18 H 33 NO3P (M+H) + : 342.2198; found: 342.2197.HPLCconditions: CHIRALPAK AD, 3% iPrOH / hexanes, 0.8 mL / min, 220 nm, t R (minor) = 26.216 min, t R(major) = 29.302 min. Example 7 ( R or S )- N,N -Diisobutyl- P methyl -(benzo[d][1,3]dioxacyclopenten-5-yl)phosphatidyl ester

[0044] The experimental procedure is the same as in Example 1.

[0045] Colorless oily substance (stirred for 48 hours in the first step, 48 mg, 73% yield, 84% ee). 1 H NMR(400 MHz, CDCl3)δ 7.31 – 7.25 (m, 1H), 7.16 (dd, J = 12.0, 1.4 Hz, 1H), 6.86 (dd, J =7.9, 3.3 Hz, 1H), 6.01 (s, 2H), 3.69 (d, J = 11.0 Hz, 3H), 2.87 – 2.72 (m, 4H), 1.89 – 1.79 (m, 2H), 0.84 (d, J = 6.6 Hz, 6H), 0.80 (d, J = 6.6 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 150.3 (d, J = 3.3 Hz), 147.8 (d, J = 21.2 Hz), 127.1 (d, J =10.1 Hz), 124.4 (d, J = 177.7 Hz), 111.5 (d, J = 11.4 Hz), 108.5 (d, J = 17.3Hz), 101.5, 53.1 (d, J = 3.9 Hz), 51.6 (d, J = 5.7 Hz), 26.6 (d, J = 2.8 Hz), 20.4 (d, J = 13.8 Hz). 31P NMR(162 MHz, CDCl3) δ 25.25;HRMS (ESI)m / z calcd forC 16 H 27 NO4P (M+H) + : 328.1678; found: 328.1675.HPLC conditions: CHIRALPAK AD, 10% i PrOH / hexane, 0.8 mL / min, 220 nm, t R (minor) = 10.520 min, t R (major) = 11.913min. Example 8 ( R or S )- N,N -Diisobutyl- P methyl 1-(1-naphthyl)phosphatidyl ester

[0046] The experimental procedure is the same as in Example 1.

[0047] Amorphous solids (62 mg, 93% yield, 96% ee). 1 H NMR (400 MHz, CDCl3) δ 8.69 (d, J = 8.5 Hz, 1H), 8.06 – 8.00 (m, 1H), 8.00 – 7.94 (m, 1H), 7.87 – 7.84 (m, 1H), 7.60 – 56 (m, 1H), 7.54 – 7.45 (m, 2H), 3.82 (d, J =10.9 Hz, 3H), 2.94 – 2.77(m, 4H), 1.86 – 1.75 (m, 2H), 0.78 (d, J = 6.7 Hz, 6H), 0.65 (d, J = 6.7 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 133.9 (d, J = 12.3 Hz), 133.7 (d, J = 7.1 Hz), 133.6 (d, J = 11.4 Hz), 132.8 (d, J = 3.3 Hz), 128.8 (d,J = 1.7 Hz), 127.3,127.2, 127.0 (d, J = 170.4 Hz), 126.3, 124.4 (d, J = 15.2 Hz), 52.7 (d, J = 3.9Hz), 52.2 (d, J = 5.8 Hz), 26.4 (d, J = 2.7 Hz), 20.3 (d, J = 49.8 Hz). 31 P NMR (162 MHz, CDCl3) δ 25.28. HPLC conditions: CHIRALPAKAD, 3% iPrOH / hexanes, 0.8mL / min, 220 nm, t R (minor) = 13.573 min, t R (major) = 19.875 min. Example 9 ( R or S )- N,N -Diisobutyl- P methyl benzylphosphazene The experimental procedure is the same as in Example 1.

[0048]

[0049] Colorless oily liquid (53.4 mg, 90% yield, 75% ee). 1 H NMR (400 MHz, CDCl3) δ 7.35 –7.19 (m, 5H), 3.54 (d, J = 10.8 Hz, 3H), 3.17 (dd, J = 20.1, 14.8 Hz, 1H), 3.07(dd, J = 18.8, 14.8 Hz, 1H), 2.85 – 2.68 (m, 4H), 1.88 – 1.77 (m, 2H), 0.88(d, J = 6.6 Hz, 6H), 0.85 (d, J = 6.6 Hz, 6H). 13 C NMR(101 MHz, CDCl3) δ 132.9(d, J= 8.4 Hz), 130.1 (d, J = 6.4 Hz), 128.5 (d, J = 2.7 Hz), 126.6 (d, J = 3.3Hz), 53.4 (d, J = 3.5 Hz), 51.1 (d, J = 7.2 Hz), 34.5 (d, J = 126.9 Hz), 26.8 (d, J = 2.5 Hz), 20.5 (d, J = 12.5 Hz). 31 P NMR(162 MHz, CDCl3) δ 32.59.HRMS (ESI)m / z calcd for C 16 H 28 NO2NaP (M+Na) + : 320.1755; found: 320.1754.HPLC conditions:CHIRALPAK ODH, 3% iPrOH / hexanes, 0.8 mL / min, 220 nm, t R (minor) = 31.526 min,t R (major) = 9.618 min. Example 10 ( R or S )- N,N -di-n-propyl- P methyl benzylphosphazene The experimental procedure is the same as in Example 1.

[0050]

[0051] Colorless oily liquid (56 mg, 98% yield, 12% ee). 1 H NMR (400 MHz, CDCl3) δ 7.72 –7.63 (m, 2H), 6.93 (dd, J = 8.7, 3.0 Hz, 2H), 3.84 (s, 3H), 3.70 (d, J = 11.1Hz, 3H), 3.06 – 2.85 (m, 4H), 1.54 – 1.44 (m, 4H), 0.82 (t, J = 7.4 Hz, 6H).13 CNMR(101 MHz, CDCl3) δ 162.1 (d, J = 3.0 Hz), 133.4 (d, J = 10.4 Hz), 122.6 (d, J = 182.2 Hz), 113.9 (d, J = 15.1 Hz), 55.3, 50.9 (d, J = 5.9 Hz), 47.1 (d, J =4.4 Hz), 22.0 (d, J = 2.1 Hz), 11.4. 31 P NMR(162 MHz, CDCl3) δ 25.64.HRMS (ESI)m / z calcd for C 14 H 25 NO3P (M+H) + : 286.1572; found: 286.1570.HPLCconditions:CHIRALPAK ODH, 5% iPrOH / hexanes, 0.8 mL / min, 220 nm, t R (minor) = 12.117 min,t R (major) = 15.936 min. Example 11 ( R or S )- N -Benzyl- N- Methyl isopropyl-P-(4-methoxyphenyl)phosphonamide The experimental procedure is the same as in Example 1.

[0052]

[0053] Colorless oily liquid (61.1 mg, 92% yield, 90% ee). 1 H NMR (400 MHz, CDCl3) δ 7.75 –7.70 (m, 2H), 7.37 – 7.21 (m, 5H), 6.94 (d, J =5.7 Hz, 2H), 4.23 (dd, J =11.0,3.6 Hz, 2H), 3.84 (s, 3H), 3.75 – 3.65 (m, 4H), 1.03 (d, J= 6.6 Hz, 3H), 0.97(d, J = 6.6 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 162.3 (d, J = 3.1 Hz), 141.38, 133.7 (d, J = 10.5 Hz), 128.3, 128.0, 126.9, 122.5 (d, J =186.1 Hz), 114.1 (d, J =14.2Hz), 55.4, 51.5, 47.8, 45.6, 21.9 (d, J =40.7 Hz). 31 P NMR(162 MHz, CDCl3) δ25.98.HRMS (ESI)m / z calcd for C 18 H 24 NO3NaP(M+Na) + :356.1391; found:356.1391.HPLCconditions: CHIRALPAKODH, 3% iPrOH / hexanes, 0.8 mL / min, 220 nm, t R (minor) = 36.353 min, t R (major) = 41.476 min. Example 12 ( R or S )- N,N -Dibenzyl- P methyl phosphonamide (4-methoxyphenyl) The experimental procedure is the same as in Example 1.

[0054]

[0055] Colorless oily liquid (71 mg, 93% yield, 94% ee). 1 H NMR (400 MHz, CDCl3) δ 7.76 –7.71 (m, 2H), 7.31 – 7.16 (m, 10H), 7.01 – 6.91 (m, 2H), 4.08 (d, J =9.9 Hz,4H), 3.85 (s, 3H), 3.72 (d, J =11.1 Hz, 3H). 13C NMR (101 MHz, CDCl3) δ 162.5 (d, J =3.4 Hz), 137.6 (d, J =2.6 Hz), 133.9 (d, J = 10.8 Hz), 128.8, 128.5, 127.4,121.7 (d, J =182.3 Hz), 114.2 (d, J = 15.4 Hz), 55.4, 51.8 (d, J =5.8 Hz), 47.9(d, J =5.0 Hz). 31 P NMR(162 MHz, CDCl3) δ 25.86.HRMS (ESI)m / z calcd for C 22 H 25 NO3P(M+H) + : 382.1572; found: 382.1575.HPLC conditions: CHIRALPAK AD, 5% iPrOH / hexanes, 0.8 mL / min, 254 nm, t R (minor) = 96.205 min, t R (major) = 69.786 min. Example 13 ( R or S )- N,N -Diisobutyl- P -(4-methoxyphenyl)phosphonamide isopropyl ester The experimental procedure is the same as in Example 1.

[0056]

[0057] Colorless oily liquid (62 mg, 91% yield, 97% ee). 1 H NMR(400 MHz, CDCl3) δ 7.69(dd, J = 11.6, 8.7 Hz, 2H), 6.94 – 6.91 (m, 2H), 4.62 – 4.53 (m, 1H), 3.84 (s,3H), 2.83 – 2.73 (m, 4H), 1.86 – 1.79 (m, 2H), 1.37 (d, J = 6.2Hz, 3H), 1.24(d,J = 6.2 Hz, 3H), 0.82 (d, J = 6.6 Hz, 6H), 0.77 (d, J = 6.6 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 162.0 (d, J = 3.2 Hz), 133.9 (d, J = 10.4 Hz), 124.0 (d, J =178.7 Hz), 113.6 (d, J = 14.9 Hz), 69.4 (d, J = 5.4 Hz), 55.4, 53.1 (d, J = 3.9Hz), 26.7 (d, J = 2.9 Hz), 24.5 (d, J = 4.1 Hz), 24.1 (d, J = 4.9 Hz), 20.4 (d, J = 16.8 Hz). 31 P NMR(162 MHz, CDCl3) δ 22.89.HRMS (ESI)m / z calcd for C 18 H 33 NO3P (M+H) + : 342.2198, found 342.2196.HPLC conditions: CHIRALPAK ADH, 3% iPrOH / hexanes, 0.8 mL / min, 220 nm, t R (minor) = 19.342 min, t R (major) = 17.220 min. Example 14 ( R or S )- N,N -Diisobutyl- P -(4-methoxyphenyl)phosphonamide n-hexyl ester

[0058] Under inert gas protection, a 10 mL Slank tube was dried by heating with a hot air gun under reduced pressure and then cooled to room temperature; this drying process was repeated three times. Under inert gas protection, the following reagents were added sequentially to the tube: chiral bicyclic imidazole catalyst (0.03 mmol), 4 Å molecular sieve (70 mg), diisobutylamine (0.70 mmol, 3.50 equivalent), and anhydrous ethylene glycol dimethyl ether (1 mL). The reaction tube was sealed with a rubber stopper (reinforced with a Parafilm membrane) and purged with inert gas. The reaction mixture was cooled to -50 °C and stirred at this temperature for 20 minutes. Subsequently, a phosphonyl dichloride substrate solution (28 μL, 0.20 mmol, 1.0 equivalent) dissolved in anhydrous CPME (methylcyclopentyl ether, 1.5 mL) was added via syringe, and the reaction was continued to be stirred at -50 °C for 36 hours.

[0059] A double-necked round-bottom flask, dried in an oven and equipped with a magnetic stirrer, was placed under an inert gas atmosphere. Hexanol (2.0 mmol) and anhydrous tetrahydrofuran (1 mL) were added to the flask, and the flask was then cooled in an ice-water bath. Sodium hydride (88 mg, 2.20 mmol, 11.0 equivalent, 60% mineral oil dispersion) was added in three batches. The flask was immediately sealed with a rubber stopper and reinforced with a sealing film. The resulting mixture was stirred at room temperature for 30 minutes. The prepared mixture was then added directly to a pre-prepared catalytic reaction system maintained at -50°C. After stirring at -50°C for 12 hours, the reaction solution was filtered through a diatomaceous earth filter to remove insoluble salts and molecular sieves. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography using silica gel.

[0060] Colorless oily liquid (75 mg, 98% yield, 95% ee). 1 H NMR(400 MHz, CDCl3) δ 7.67(dd, J =11.9, 8.7 Hz, 2H), 6.93 (dd, J =8.7, 3.0 Hz, 2H), 4.02 – 3.88 (m, 2H),3.84 (s, 3H), 2.87 – 2.72 (m, 4H), 1.88 – 1.80 (m, 2H), 1.71 – 1.64 (m, 2H),1.43 – 1.26 (m, 9H), 0.83 (d, J = 6.6 Hz, 6H), 0.79 (d, J = 6.6 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 162.0 (d, J=3.3 Hz), 133.8 (d, J =10.4 Hz), 123.1 (d, J =178.7Hz), 113.8 (d, J =14.9 Hz), 64.8 (d, J =5.6 Hz), 55.4, 53.1 (d, J =4.0 Hz), 31.5,30.6 (d, J =7.0 Hz), 26.7 (d, J =2.9 Hz), 25.5, 22.7, 20.4 (d, J =13.1 Hz), 14.12. 31 P NMR(162 MHz, CDCl3) δ 24.12.HRMS (ESI)m / z calcd for C 21 H 39 NO3P (M+H) + :384.2668; found:384.2667. Example 15 ( R or S )- N,N -Diisobutyl- P 4-(4-methoxyphenyl)phosphonamide phenyl ester

[0061] Under inert gas protection, a 10 mL Slank tube was dried by heating with a hot air gun under reduced pressure and then cooled to room temperature; this drying process was repeated three times. Under inert gas protection, the following reagents were added sequentially to the tube: chiral bicyclic imidazole catalyst (0.03 mmol), 4 Å molecular sieve (70 mg), diisobutylamine (0.70 mmol, 3.50 equivalent), and anhydrous ethylene glycol dimethyl ether (1 mL). The reaction tube was sealed with a rubber stopper (reinforced with a Parafilm membrane) and purged with inert gas. The reaction mixture was cooled to -50 °C and stirred at this temperature for 20 minutes. Subsequently, a phosphonyl dichloride substrate solution (28 μL, 0.20 mmol, 1.0 equivalent) dissolved in anhydrous CPME (methylcyclopentyl ether, 1.5 mL) was added via syringe, and the reaction was continued to be stirred at -50 °C for 36 hours.

[0062] A double-necked round-bottom flask, dried in an oven and equipped with a magnetic stirrer, was placed under an inert gas atmosphere. Phenol (2.0 mmol) and anhydrous tetrahydrofuran (1 mL) were added to the flask, and the reaction flask was then cooled in an ice-water bath. Sodium hydride (88 mg, 2.20 mmol, 11.0 equivalent, 60% mineral oil dispersion) was added in three batches. The flask was immediately sealed with a rubber stopper and reinforced with sealing film. The resulting mixture was stirred at room temperature for 60 minutes.

[0063] Separately, a double-necked round-bottom flask dried in an oven and equipped with a magnetic stirrer was used. Silver carbonate (20.0 mol%) and anhydrous tetrahydrofuran (0.5 mL) were added under an inert gas atmosphere, and the mixture was ultrasonically dispersed to form a homogeneous suspension (without macroscopically visible solid particles). This homogeneous suspension was added in one go to a pre-prepared catalytic reaction system maintained at -50°C. After 1 minute, the previously prepared sodium phenolate mixture was added. Stirring was continued at -50°C for 12 hours. The reaction solution was then filtered through a diatomaceous earth filter to remove insoluble salts and molecular sieves. The filtrate was concentrated under reduced pressure, and the residue was purified by preparative thin-layer chromatography using silica gel.

[0064] Colorless oily liquid (73 mg, 97% yield, 96% ee). 1 H NMR(400 MHz, CDCl3) δ 7.80 –7.74 (m, 2H), 7.27 – 7.23 (m, 4H), 7.08 – 7.04 (m, 1H), 6.95 – 6.91 (m, 2H),3.84 (s, 3H), 2.97 – 2.81 (m, 4H), 1.88 – 1.81 (m, 2H), 0.82 (d, J = 6.7 Hz, 6H), 0.73 (d, J = 6.7 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 162.3 (d, J = 3.1 Hz), 151.8 (d, J = 7.6 Hz), 134.1 (d, J = 10.6 Hz), 129.6, 124.0, 122.3 (d, J = 183.2Hz), 120.4 (d, J = 5.1 Hz), 113.9 (d, J = 15.6 Hz), 55.4, 52.8 (d, J = 3.7 Hz), 26.6 (d, J= 2.8 Hz), 20.4 (d, J = 26.8 Hz). 31 P NMR (162 MHz, CDCl3) δ 22.02.HRMS (ESI) m / z calcd for C 21 H 31 NO3P (M+H) + :376.2042, found:376.2035.HPLCconditions: CHIRALPAK ODH, 3% iPrOH / hexanes, 0.8 mL / min, 220 nm, t R (minor) = 17.693 min, t R (major) = 12.619 min. Example 16 ( R or S )- N,N -Diisobutyl- P phenyl phosphonocarboxylate (4-trifluoromethylphenyl)phosphonamide

[0065] The experimental procedure is the same as in Example 15.

[0066] Colorless oily liquid (81 mg, 91% yield, 96% ee). 1 H NMR (400 MHz, CDCl3) δ 7.83 –7.70 (m, 2H), 7.53 (d, J =8.6 Hz, 2H), 7.34 (d, J =8.5 Hz, 2H), 7.01 – 6.92 (m,2H), 3.85 (s, 3H), 3.01 – 2.80 (m, 4H), 1.91 – 1.81 (m, 2H), 0.83 (d, J =6.6Hz, 6H), 0.76 (d, J =6.6 Hz, 6H). 13 C NMR (101 MHz, CDCl3) δ 162.6 (d, J = 3.5 Hz), 154.5 (d, J = 7.3 Hz), 134.1 (d, J = 10.7 Hz), 127.1 (q, J = 3.8 Hz), 126.2 (q,J =32.7 Hz), 124.2 (q, J = 272.6 Hz), 121.3 (d, J = 183.5 Hz), 120.5 (d, J = 5.2Hz), 114.1 (d, J = 15.7 Hz), 55.4, 52.7 (d, J = 3.9 Hz), 26.5 (d, J = 2.8 Hz), 20.3 (d, J = 24.5 Hz). 31 P NMR (162 MHz, CDCl3) δ 23.08. 19 F NMR(377 MHz, CDCl3) δ-62.01.HRMS (ESI)m / z calcd for C 22 H 29 NO3PF3Na(M+Na) + :466.1735; found466.1731.HPLC conditions: CHIRALPAK IE, 5% iPrOH / hexanes, 0.8 mL / min, 254 nm,t R (minor) = 48.092 min, t R (major) = 53.267 min. Example 17 ( R or S methyl 4-(4-methoxyphenyl)-4-(trifluoromethyl)phenylphosphonate

[0067] The compound obtained from Example 19 (443.5 mg, 1 mmol) was reacted with p-toluenesulfonic acid monohydrate ( p-TsOH·H2O (951 mg, 5.0 equivalents) was placed in a single-necked flask and dissolved in methanol (10 mL). The reaction mixture was stirred in an oil bath at 50 °C for 8 hours, and the reaction progress was monitored by thin-layer chromatography. The reaction was terminated after the starting material was completely consumed, and the reaction solution was concentrated under reduced pressure using a rotary evaporator to remove the methanol solvent. The resulting residue was diluted with ethyl acetate and extracted successively with saturated sodium bicarbonate solution, saturated ammonium chloride solution, and saturated sodium chloride solution. The combined organic phases were dried over anhydrous sodium sulfate and concentrated to obtain a crude oily mixture. Finally, the product was purified by rapid column chromatography (eluent: petroleum ether / ethyl acetate = 5:1 → 2:1) to obtain the target product (312 mg, yield 90%, enantiomeric excess 95%).

[0068] 1 H NMR (400 MHz, CDCl3) δ 7.84 – 7.78 (m, 2H), 7.55 (d, J =8.3 Hz, 2H), 7.28 (d, J =8.0 Hz, 2H), 7.01 – 6.97 (m, 2H), 3.93 – 3.75 (m, 6H). 13 C NMR(101MHz, CDCl3)δ 163.6 (d, J = 3.5 Hz), 153.3 (d, J = 6.8 Hz), 134.2 (d, J = 11.8Hz), 127.1 (q, J = 3.7 Hz), 127.0 (q, J = 33.2 Hz), 124.0 (q, J = 272.8 Hz), 120.9(d, J = 4.7 Hz), 117.3 (d, J = 199.1 Hz), 114.4 (d, J = 16.7 Hz), 55.4, 53.1 (d, J = 5.8 Hz). 31 P NMR (162 MHz, CDCl3) δ 18.24. 19 F NMR(377 MHz, CDCl3) δ -62.17.HRMS (ESI)m / z calcd for C 15 H 15 O4PF3(M+H) +: 347.0660, found: 347.0659.HPLCconditions: CHIRALPAKOJ, 10% iPrOH / hexanes, 0.8 mL / min, 220 nm, t R (minor) = 11.398 min, t R (major) = 13.694 min. Example 18 ( R or S methyl 4-ethyl-(4-methoxyphenyl)phosphinate

[0069] A clean, dry 10 mL Slank tube was subjected to a vacuum-inert gas purging cycle three times. Under inert gas protection, the compound obtained in Example 19 (0.1 mmol, 35 mg) and anhydrous tetrahydrofuran (2 mL) were added to the tube, and the mixture was stirred at -50 °C for 20 minutes. Maintaining the -50 °C temperature, a THF solution of ethyl magnesium bromide (1 mol / L, 1.2 equivalents) was slowly added dropwise using a syringe, and the reaction was continued at this temperature with stirring for 48 hours. After the reaction was complete, isopropanol (0.5 mL) was slowly added dropwise at -50 °C to quench the reaction. The mixture was brought to room temperature, diluted with ethyl acetate, and extracted successively with saturated ammonium chloride solution and saturated sodium chloride solution. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to obtain the crude product. Finally, the crude product was purified by preparative thin-layer chromatography (silica gel, eluent: petroleum ether / ethyl acetate = 4:1) to obtain the target product 5 (16 mg, yield 75%, enantiomeric excess 96%).

[0070] 1 H NMR (400 MHz, CDCl3) δ 7.74 (dd, J = 12.7, 8.4 Hz, 2H), 6.97 (dd, J =8.7, 3.4 Hz, 2H), 4.20 – 4.01 (m, 2H), 3.85 (s, 3H), 3.72 (d, J = 11.2 Hz, 3H), 1.32 (t, J = 7.0 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 163.1 (d, J = 3.4 Hz), 134.0 (d, J = 11.4 Hz), 118.8 (d, J= 195.6 Hz), 114.2 (d, J = 16.1 Hz), 62.2(d, J = 5.4 Hz), 55.5, 52.5 (d, J = 5.4 Hz), 16.4 (d, J = 6.5 Hz). 31 P NMR (162 MHz, CDCl3) δ 21.12; HRMS (ESI) m / z calcd for C 10 H 15 O3NaP (M+Na) + : 237.0657; found:237.0654.HPLC conditions: CHIRALPAKAY,10% iPrOH / hexanes, 0.8 mL / min, 220 nm,t R (minor) = 21.009 min, t R (major) = 22.685 min. Example 19 ( R or S )-O-methyl-O-(4-(trifluoromethyl)phenyl)-(4-methoxyphenyl)thiophosphonate

[0071] A clean 10 mL Slank tube was used for three cycles of vacuum evacuation followed by inert gas purging. Under inert gas protection, the compound obtained in Example 19 (35 mg, 0.1 mmol) and Lawson's reagent (81 mg, 2.0 mmol) were added to the reaction tube, followed by anhydrous toluene (2 mL). The mixture was heated under reflux for 24 hours, monitored by thin-layer chromatography until the starting material was completely consumed. After cooling to room temperature, the reaction solution was diluted with ethyl acetate and extracted successively with saturated sodium bicarbonate solution and saturated sodium chloride solution. The organic phases were combined, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. Purification was performed by preparative thin-layer chromatography (silica gel plate size: 20 cm × 20 cm, thickness 1 mm; eluent: petroleum ether / ethyl acetate = 5:1) to obtain target product 6 (23 mg, yield 63%, enantiomeric excess 95%).

[0072] 1 H NMR (400 MHz, CDCl3) δ 7.93 (dd, J = 13.1, 7.9 Hz, 2H), 7.57 – 7.54(m, 2H), 7.18 (d, J= 8.4 Hz, 2H), 7.04 – 6.93 (m, 2H), 3.90 – 3.77 (m, 6H). 13 CNMR(101 MHz, CDCl3) δ 163.5 (d, J = 3.3 Hz), 153.4 (d, J = 7.2 Hz), 133.7 (d, J =13.8 Hz), 127.3 (q, J = 32.5 Hz), 126.9 (q, J = 3.2 Hz), 124.1 (q, J = 272.9 Hz), 123.2 (d, J = 159.9 Hz), 122.0 (d, J = 4.7 Hz), 114.1 (d, J = 16.6 Hz), 55.6,53.6 (d, J = 5.7 Hz). 31 P NMR (162 MHz, CDCl3) δ 88.05. 19 F NMR(377 MHz, CDCl3) δ -62.22.HRMS (ESI)m / z calcd for C 15 H 15 O3SPF3(M+H) + : 363.0432; found:363.0428.HPLC conditions: CHIRALPAKOJ, 10% iPrOH / hexanes, 0.8 mL / min, 254 nm,t R (minor) = 21.458 min, t R (major) = 23.248 min. Example 20 ( R or S methyl phosphonate (2-hydroxy-4-(trifluoromethyl)phenyl)-(4-methoxyphenyl)phosphonate

[0073] A clean, dry 10 mL Slank tube was subjected to a vacuum-inert gas purging cycle three times. Under an inert gas atmosphere, the compound obtained in Example 19 (35 mg, 0.10 mmol) was dissolved in anhydrous tetrahydrofuran (2 mL), and the mixture was stirred at -78 °C for 20 minutes. While maintaining the -78 °C temperature, LDA (1.2 equivalents, 2.0 M tetrahydrofuran / n-hexane solution) was slowly added dropwise via a syringe, and the reaction was continued at this temperature with stirring for 50 hours. After the reaction was complete, isopropanol (0.5 mL) was slowly added dropwise at -78 °C to quench the reaction. The resulting mixture was concentrated under reduced pressure, and the crude product was purified by preparative thin-layer chromatography (silica gel, developing solvent: n-hexane / ethyl acetate = 10:1 → 5:1) to give compound 7 (24 mg, 70% yield) as a white solid.

[0074] 1 H NMR (400 MHz, CDCl3) δ 11.44 (s, 1H), 7.86 – 7.72 (m, 2H), 7.62 (d, J = 8.7 Hz, 1H), 7.42 (d, J = 12.9 Hz, 1H), 7.06 – 7.00 (m, 3H), 3.86 (s, 3H), 3.81 (d, J = 11.6 Hz, 3H). 13 C NMR (101 MHz, CDCl3) δ 165.7 (d, J = 5.3 Hz), 163.7(d, J = 3.1 Hz), 133.5 (d, J = 12.0 Hz), 132.5 – 131.3 (m), 130.4 – 128.5 (m), 124.0 (q, J = 272.1 Hz), 122.1 (dd, J = 33.1, 13.1 Hz), 120.7 (d, J = 155.2 Hz), 118.9 (d, J = 9.1 Hz), 114.7 (d, J = 14.9 Hz), 111.7 (d, J = 130.4 Hz), 55.6,52.2 (d, J = 6.2 Hz). 31 P NMR (162 MHz, CDCl3) δ 40.15. 19F NMR(377 MHz, CDCl3) δ -61.75.HRMS (ESI)m / z calcd for C 15 H 14 O4NaPF3(M+Na) + : 369.0479; found369.0475.HPLC conditions: CHIRALPAK IC3, 10% iPrOH / hexanes, 0.8 mL / min, 220nm, tR(minor) = 26.175 min, tR(major) = 23.047 min. This invention is not limited to the preferred embodiments described above. Anyone can derive other forms of products under the guidance of this invention. However, regardless of any changes made in their shape or structure, any technical solution that is the same as or similar to this application falls within the protection scope of this invention.

Claims

1. A phosphonamide compound having a pentavalent chiral phosphorus center, characterized in that, The structural formula of the phosphonamide compound is shown in (V): ， Among them, the chiral configuration of phosphorus marked with * is R or S The R group includes C7-C8 alkyl or C6-C13 aryl groups. 1 and R 2 The groups include either alkyl or aryl substituents.

2. The phosphonamide compound having a pentavalent phosphorus chiral center according to claim 1, characterized in that: The aromatic ring in the C6-C13 aryl group is replaced by one or two C1-C7 hydrocarbon groups.

3. The phosphonamide compound having a pentavalent phosphorus chiral center according to claim 1 or 2, characterized in that: The aromatic ring of the C6-C13 aryl group, or the aromatic ring of the C6-C13 aryl group, after being replaced by one or two C1-C7 hydrocarbon groups, is further replaced by one or more substituents independently selected from halogen, alkoxy, trifluoromethyl, phenyl or phenoxy.

4. The phosphonamide compound having a pentavalent phosphorus chiral center according to claim 1, characterized in that, The structural formulas of the phosphonamide compounds include: 。 5. The method for synthesizing the phosphonamide compound having a pentavalent phosphorus chiral center according to any one of claims 1-4, characterized in that: Phosphonyl dichloride (Ⅰ) and secondary amine (Ⅱ) were synthesized in a one-pot manner via enantioselective amino substitution followed by the addition of a nucleophile (Ⅳ) and additives, under the catalysis of a chiral bicyclic imidazole. The synthesis route is shown below. ， Among them, in the secondary amine raw material (II), R 1 and R 2 The groups include any one of ethyl, n-propyl, isopropyl, n-butyl, isobutyl, benzyl, phenyl, or substituted phenyl groups.

6. The method for synthesizing the phosphonamide compound having a pentavalent phosphorus chiral center according to claim 5, characterized in that, The structural formula of the chiral bicyclic imidazole catalyst is shown below: ， In this case, the chiral configuration of the C atom marked with * is R or S, and Ar is aryl.

7. The method for synthesizing phosphonamide compounds having a pentavalent chiral phosphorus center according to claim 6, characterized in that: The nucleophile NuH includes one of the following: alcohols, thiols, phenols, thiophenols, primary amines, secondary amines, Grignard reagents, or their corresponding sodium salts, NuNa.

8. The method for synthesizing phosphonamide compounds having a pentavalent chiral phosphorus center according to claim 6, characterized in that: The additive is an inorganic salt, including one of silver nitrate, silver carbonate, silver hexafluoroantimonate, potassium chloride, and sodium chloride.

9. A method for preparing a highly enantioselective chiral pentavalent phosphine compound, based on a phosphonamide compound (V) having a pentavalent phosphorus chiral center according to any one of claims 1-8, characterized in that: Phosphamide compound (V) was subjected to alcoholysis to break the PN bond and form a PO bond, thereby obtaining a highly enantioselective chiral pentavalent phosphine compound; the structural formula of the highly enantioselective chiral pentavalent phosphine compound is shown in (VI): ， Among them, R 3 The groups include alkyl and benzoynyl groups, and the alkyl groups include one of methyl, ethyl, n-propyl, isopropyl, and n-butyl.

10. The method for preparing a highly enantioselective chiral pentavalent phosphine compound according to claim 9, characterized in that: The compound (VI) undergoes a nucleophilic substitution reaction with an organolithium reagent, and after rearrangement, generates a compound (VII) with a new PC (Ar) bond; the compound (VI) reacts with Lawson's reagent to generate a compound (VIII) with a new P=S bond; the compound (VI) reacts with Grignard reagent to generate a compound (IX) with a new PC bond. ， Among them, R 4 Groups include electron-donating and electron-withdrawing groups. Electron-donating groups include one of methyl, ethyl, n-propyl, methoxy, and ethoxy groups, while electron-withdrawing groups include one of trifluoromethyl, nitro, and halogen groups; R 5 Groups include alkyl, alkoxy, allyl, and benzoynyl.

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