A symmetrical phosphinic acid compound, a symmetrical phosphinic acid amino acid derivative, and preparation method and application thereof

Abstract

The invention provides a symmetrical phosphinic acid compound, a symmetrical phosphinic acid amino acid derivative, and a preparation method and application thereof. The invention constructs a symmetrical phosphinic acid amino acid derivative shown in formula H by constructing a symmetrical phosphinic acid compound structural module, and obtains a symmetrical phosphinic acid amino acid derivative shown in formula I by deprotection. The derivative has a wide range of potential biological application prospects, including being used as an enzyme inhibitor or a receptor agonist / antagonist, having a high inhibitory effect on HIV-1 protease, being able to reduce the proliferation and activation of mouse and human T cells, and having a potential immunoregulatory effect, and provides a valuable reference for further evaluating the potential of these compounds as antidepressants, anti-inflammatory drugs, anti-Alzheimer's disease drugs, antiparasitic drugs, anti-hepatitis drugs, antiproliferative drugs, anti-influenza drugs, anti-HIV drugs, antimalarial drugs and antimicrobial drugs.

Description

Technical Field

[0001] The invention belongs to the technical field of compound synthesis and relates to a symmetrical phosphinic acid compound, a symmetrical phosphinic acid amino acid derivative and a preparation method and application thereof. Background Art

[0002] Phosphinic acid derivatives exhibit a variety of biological activities and have a high degree of structural diversity, which makes them versatile tools for the design and development of new drugs. Phosphinic acid has a wide range of applications in medicinal chemistry and can be used as antidepressants, anti-inflammatory drugs, anti-Alzheimer's drugs, antiparasitic drugs, anti-hepatitis drugs, antiproliferative drugs, anti-influenza drugs, anti-HIV drugs, antimalarial drugs, antimicrobial agents, etc. (Abdou, M. et al, Phosphinic acids: current status and potential for drug discovery. Drug Discovery Today, 2019, 916-929). The synthesis methods of these compounds have been introduced in the prior art (Yiotakis, A. et al, Phosphinic Peptides: Synthetic Approaches and Biochemical Evaluation as Zn-Metalloprotease Inhibitors, Current Organic Chemistry, 2004, 1135-1158, Talma, M. et al, Recent developments in the synthesis and applications of phosphinic peptide analogs, Bioorganic & Medicinal Chemistry Letters, 2019, 1031-1042). The current synthesis method has many steps, a long process, and a low product yield, which makes phosphinic acid unsuitable for commercialization.

[0003] Therefore, in this field, the development of a simple and efficient method for synthesizing phosphinic acid remains a research focus. Summary of the invention

[0004] In view of the deficiencies in the prior art, the present invention aims to provide a symmetrical phosphinic acid compound and a preparation method and application thereof.

[0005] To achieve this object, the present invention adopts the following technical solutions:

[0006] In one aspect, the present invention provides a symmetrical phosphinic acid compound having a structure as shown in the following formula C:

[0007]

[0008] Wherein R is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C30 aryl, and Et represents ethyl.

[0009] In some preferred technical solutions, R in formula C is selected from hydrogen, methyl, sec-butyl, isopropyl, benzyl or In the present invention, a wavy line represents the attachment site of a group.

[0010] In some preferred technical solutions, the symmetrical phosphinic acid compound is any one of the following compounds 4a-4e:

[0011]

[0012] On the other hand, the present invention provides a method for preparing the symmetrical phosphinic acid compound as described above, the preparation method comprising the following steps:

[0013] (1) ammonium phosphinate reacts with the acrylic acid ester compound of formula A to obtain a compound of formula B, and the reaction formula is as follows:

[0014]

[0015] (2) The compound represented by formula B reacts with the acrylic acid ester compound represented by formula A to obtain the compound represented by formula C. The reaction formula is as follows:

[0016]

[0017] Preferably, the molar ratio of the ammonium phosphite in step (1) to the acrylate compound of formula A is 5:2.

[0018] Preferably, the reaction in step (1) is carried out in the presence of hexamethyldisilazane (HMDS).

[0019] Preferably, the molar ratio of hexamethyldisilazane to ammonium phosphinate is 4:2.5.

[0020] Preferably, the reaction in step (1) is carried out in a solvent selected from dichloromethane and / or chloroform.

[0021] Preferably, the reaction in step (1) is to mix ammonium phosphinate and hexamethyldisilazane for reaction, and then dropwise add an acrylic ester compound for reaction to obtain a compound represented by formula B.

[0022] Preferably, the mixed reaction of ammonium phosphinate and hexamethyldisilazane is carried out at a temperature of 110° C. and the reaction time is 1 hour.

[0023] Preferably, after the mixed reaction of the ammonium phosphinate and hexamethyldisilazane is completed, the reaction mixture is cooled to 0° C., a solvent is added, and then a solution of an acrylic ester compound is added dropwise to react to obtain a compound represented by formula B.

[0024] Preferably, the solvent is dichloromethane and / or chloroform.

[0025] Preferably, the solution of the acrylate compound is a dichloromethane or chloroform solution of the acrylate compound.

[0026] Preferably, the reaction after adding the acrylic acid ester compound is carried out at room temperature (15-35°C, for example 15°C, 18°C, 20°C, 25°C, 30°C or 35°C), and the reaction time is 24-48h (for example 24h, 28h, 30h, 33h, 36h, 40h, 42h, 44h, 46h or 48h).

[0027] Preferably, the reaction in step (1) is carried out under nitrogen protection.

[0028] Preferably, the molar ratio of the compound represented by formula B in step (2) to the acrylate compound represented by formula A is 1:1.2.

[0029] Preferably, the reaction in step (2) is carried out in the presence of an alkaline substance.

[0030] Preferably, the alkaline substance is selected from triethylamine.

[0031] Preferably, the reaction in step (2) is carried out in a solvent selected from dichloromethane and / or chloroform. Preferably, the reaction in step (2) is carried out in the presence of 2,4,6-trimethylbenzenesulfonyl chloride (TMSCl).

[0032] Preferably, the molar ratio of the 2,4,6-trimethylbenzenesulfonyl chloride to the compound represented by formula B is 7:1.

[0033] Preferably, the reaction in step (2) is carried out at room temperature (15-35°C, for example 15°C, 18°C, 20°C, 25°C, 30°C or 35°C), and the reaction time is 48-72h (for example 48h, 50h, 53h, 55h, 58h, 60h, 64h, 68h, 70h or 72h).

[0034] In another aspect, the present invention provides a symmetrical phosphinic acid compound having a structure shown in the following formula D:

[0035]

[0036] Wherein R is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C30 aryl, and Et represents ethyl.

[0037] In some preferred technical solutions, R in formula D is selected from hydrogen, methyl, sec-butyl, isopropyl, benzyl or

[0038] On the other hand, the present invention provides a method for preparing a symmetrical phosphinic acid compound represented by formula D, the preparation method comprising the following steps:

[0039] The compound represented by formula C reacts with 1-bromoadamantane to obtain the compound represented by formula D. The reaction formula is as follows:

[0040]

[0041] Preferably, the molar ratio of the compound represented by formula C to 1-bromoadamantane is 1:1.2.

[0042] Preferably, the reaction of the compound represented by formula C and 1-bromoadamantane is carried out in a solvent selected from chloroform. Preferably, the reaction of the compound represented by formula C and 1-bromoadamantane is carried out in the presence of a catalyst.

[0043] Preferably, the catalyst is selected from silver oxide.

[0044] Preferably, the molar ratio of the catalyst to the compound represented by formula C is 1.2:1.

[0045] Preferably, the specific operation of the reaction of the compound represented by formula C and 1-bromoadamantane is: dissolving the compound represented by formula C and 1-bromoadamantane in a solvent, refluxing the solution, and then adding the catalyst to the refluxing solution, continuing the reflux reaction, to obtain the compound represented by formula D.

[0046] Preferably, the solution is refluxed for 10-30 min, such as 10 min, 15 min, 20 min, 25 min or 30 min before the catalyst is added.

[0047] Preferably, the reflux reaction is continued for 5-12 h after the catalyst is added, for example, 5 h, 6 h, 8 h, 10 h or 12 h.

[0048] In another aspect, the present invention provides a symmetrical phosphinic acid compound having a structure shown in the following formula E:

[0049]

[0050] Wherein, R is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C30 aryl.

[0051] In some preferred technical solutions, R in formula E is selected from hydrogen, methyl, sec-butyl, isopropyl, benzyl or

[0052]

[0053] On the other hand, the present invention provides a method for preparing the symmetrical phosphinic acid compound as shown in the above formula E, the preparation method comprising the following steps:

[0054] The compound represented by formula D is hydrolyzed to obtain the compound represented by formula E, and the reaction formula is as follows:

[0055]

[0056] Preferably, the hydrolysis reaction is carried out in a solvent selected from methanol,

[0057] Preferably, the hydrolysis reaction is carried out in the presence of an alkaline substance.

[0058] Preferably, the alkaline substance is selected from lithium hydroxide.

[0059] Preferably, the hydrolysis reaction is carried out at room temperature (15-35°C, such as 15°C, 18°C, 20°C, 25°C, 30°C or 35°C), and the hydrolysis reaction time is 12-24h, such as 12h, 15h, 18h, 20h, 22h or 24h.

[0060] In another aspect, the present invention provides a symmetrical phosphinic acid amino acid derivative, wherein the symmetrical phosphinic acid amino acid derivative has a structure as shown in the following formula H:

[0061]

[0062] Wherein R is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C30 aryl, and R' is selected from amino acid side chains.

[0063] In some preferred embodiments, R in formula H is selected from hydrogen, methyl, sec-butyl, isopropyl, benzyl or

[0064] In the present invention, R' can be derived from any one of the 20 natural amino acids, and R' is selected from the side chain of any one of the 20 natural amino acids;

[0065] In some preferred embodiments, R' is selected from a glycine side chain, an alanine side chain, a valine side chain, a leucine side chain, a phenylalanine side chain, or a proline side chain.

[0066] In some preferred embodiments, the symmetrical phosphinic acid amino acid derivative is selected from any one of the following compounds 8a-8g:

[0067]

[0068] On the other hand, the present invention provides a method for preparing the symmetrical phosphinic acid amino acid derivative as described above, the preparation method comprising the following steps:

[0069] The compound represented by formula E reacts with the compound represented by formula F to obtain the compound represented by formula H. The reaction formula is as follows:

[0070]

[0071] Preferably, the molar ratio of the compound represented by formula E to the compound represented by formula F is 1:2.2.

[0072] Preferably, the reaction of the compound represented by formula E and the compound represented by formula F is carried out in the presence of a basic substance.

[0073] Preferably, the alkaline substance is selected from N,N-diisopropylethylamine (DIPEA).

[0074] Preferably, the reaction of the compound represented by formula E and the compound represented by formula F is carried out in the presence of an activating agent.

[0075] Preferably, the activator is selected from 1-hydroxybenzotriazole (HOBt) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC·HCl).

[0076] Preferably, the reaction of the compound represented by Formula E and the compound represented by Formula F is carried out in a solvent, and the solvent is selected from dichloromethane and / or chloroform.

[0077] Preferably, the reaction of the compound represented by formula E with the compound represented by formula F is carried out at room temperature (15-35°C, for example 15°C, 18°C, 20°C, 25°C, 30°C or 35°C), and the reaction time is 12-24h (for example 12h, 15h, 18h, 20h, 23h or 24h).

[0078] In another aspect, the present invention provides a symmetrical phosphinic acid amino acid derivative, wherein the symmetrical phosphinic acid amino acid derivative has a structure as shown in the following formula I:

[0079]

[0080] Wherein R is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C30 aryl, and R' is selected from amino acid side chains.

[0081] Preferably, R' is selected from the group consisting of a glycine side chain, an alanine side chain, a valine side chain, a leucine side chain, a phenylalanine side chain or a proline side chain.

[0082] As a preferred technical solution, the symmetrical phosphinic acid amino acid derivative includes any one of the following compounds 9a-9g:

[0083]

[0084] On the other hand, the present invention provides a method for preparing the symmetrical phosphinic acid amino acid derivative as described above, the preparation method comprising the following steps:

[0085] The compound represented by formula H is subjected to a deprotection reaction to obtain a compound represented by formula I. The reaction formula is as follows:

[0086]

[0087] Preferably, the deprotection reaction is carried out in the presence of an acid, preferably trifluoroacetic acid.

[0088] Preferably, the deprotection reaction is carried out in the presence of a carbocation capture agent;

[0089] Preferably, the carbocation capture agent is selected from triisopropylsilane and water;

[0090] Preferably, the deprotection reaction is carried out in a solvent, and the solvent is dichloromethane.

[0091] Preferably, the deprotection reaction is to treat the compound represented by formula H with a mixture of dichloromethane, trifluoroacetic acid, triisopropylsilane and water, and react at room temperature (15-35°C, for example, 15°C, 18°C, 20°C, 25°C, 30°C or 35°C) for 12-24h (for example, 12h, 15h, 18h, 20h, 23h or 24h) to obtain the compound represented by formula I.

[0092] Preferably, the volume ratio of dichloromethane, trifluoroacetic acid, triisopropylsilane and water is 50:50:0.1:0.1.

[0093] In another aspect, the present invention provides the use of the symmetrical phosphinic acid amino acid derivative represented by formula I described above in the preparation of HIV-1 protease inhibitors.

[0094] In another aspect, the present invention provides the use of the symmetrical phosphinic acid amino acid derivative represented by formula I as described above in the preparation of an inhibitor of T cell proliferation and activation.

[0095] Compared with the prior art, the present invention has the following beneficial effects:

[0096] The present invention constructs a symmetrical phosphinic acid compound structural module (such as formula CE) to further construct a symmetrical phosphinic acid amino acid derivative shown in formula H, and obtains a symmetrical phosphinic acid amino acid derivative shown in formula I by deprotection. The derivative has a wide range of potential biological application prospects, including being used as an enzyme inhibitor or receptor agonist / antagonist, having a high inhibitory effect on HIV-1 protease, being able to reduce the proliferation and activation of mouse and human T cells, and having a potential immunoregulatory effect, and provides a valuable reference for further evaluating the potential of these compounds as antidepressants, anti-inflammatory drugs, anti-Alzheimer's disease drugs, antiparasitic drugs, anti-hepatitis drugs, antiproliferative drugs, anti-influenza drugs, anti-HIV drugs, antimalarial drugs and antimicrobial drugs. BRIEF DESCRIPTION OF THE DRAWINGS

[0097] Figure 1 This is a graph showing the test results of the HIV-1 protease inhibitory activity of the compounds prepared by the present invention, wherein A is the relative inhibitory activity of compounds 9a-9f on HIV-1 protease at concentrations of 1 μM, 100 nM and 10 nM; wherein the data range line represents the mean ± SD, n = 2; B is the inhibitory activity of compound 9c on HIV-1 protease, wherein the data range line represents the mean ± SD, n = 3.

[0098] Figure 2A is the effect of phosphinic acid derivatives on T cell activity, wherein C1-C7 represent the test results of compounds 9a-9g, respectively;

[0099] Figure 2B : is the effect of phosphinate derivatives on T cell proliferation, wherein C1-C7 represent the test results of compounds 9a-9g respectively. DETAILED DESCRIPTION

[0100] The technical solution of the present invention is further described below by specific implementation methods. It should be understood by those skilled in the art that the embodiments are only to help understand the present invention and should not be regarded as specific limitations of the present invention.

[0101] Synthesis Example

[0102] In the following synthesis example, the synthesis route is as follows:

[0103]

[0104] The general steps for the synthesis of 3a-e are as follows:

[0105] In a dried flask, NH4H2PO2 (4.52 g, 39.25 mmol, 2.5 eq) and HMDS (13.1 ml, 62.8 mmol, 4 eq) were heated at 110°C for 1 h under a continuous flow of N2 until a clear solution was formed. Subsequently, the reaction mixture was cooled to 0°C and anhydrous DCM (40 ml) was added. Over 20 min, a solution of acrylate 2a-e (15.7 mmol, 1 eq) in anhydrous DCM (20 mL) was added dropwise to the cold stirred mixture. The mixture was reacted under stirring at room temperature, and the reaction progress was monitored by TLC. After the reaction was completed (reaction time was 24-48 h), MeOH was slowly added at 0°C.

[0106] (40 ml) and stirring was continued at room temperature for 30 min. The volatiles were evaporated in vacuo, the residue was acidified to pH 1 with 3M HCl, dissolved in DCM and washed with 1M HCl, and the organic phase was dried over Na2SO4 and concentrated in vacuo to give the product as a light yellow oil.

[0107] In the synthesis of 3a-e, each compound is synthesized using a starting acrylate 2a-e having a corresponding group.

[0108] The structures and characterization data of compounds 3a-e are as follows:

[0109] (3-Ethoxy-3-oxypropyl)phosphinic acid (3a)

[0110]

[0111] Chemical formula: C5H11O4P, exact molecular weight: 166.0395, molar molecular weight: 166.1128.

[0112] Light yellow viscous oil, yield 99%. Rf (DCM / MeOH / AcOH=7 / 0.7 / 0.15) 0.29. 1 H NMR (400

[0113] MHz, CDCl3) δ7.18 (d, J = 564Hz, 1H), 4.14 (q, J = 7.2Hz, 2H), 2.61 (dt, J = 15.5, 7.5Hz, 2H),

[0114] 2.05(dtd,J=14.9,7.7,2.1Hz,2H), 1.24(t,J=7.2Hz,3H). 13 C NMR (101MHz, CDCl3) δ171.9 (d, J = 13.1Hz), 61.2, 26.1 (d, J = 3.0Hz), 24.4 (d, J = 95.9Hz), 14.1. 31P NMR (162MHz,CDCl3)δ35.5.C5H 10 O4P - , [M–H] - MS (ESI) m / z calcd. 165.0, found 165.0.

[0115] (3-Ethoxy-2-methyl-3-oxypropyl)phosphinic acid (3b)

[0116]

[0117] Chemical formula: C6H13O4P, exact molecular weight: 180.0551, molar molecular weight: 180.1398.

[0118] Light yellow viscous oil, yield 99%. Rf (DCM / MeOH / AcOH=7 / 0.7 / 0.15) 0.32. 1 H NMR (400 MHz, CDCl3) δ7.17 (d, 1 J P-H =564Hz,1H),4.13(q,J=7.2Hz,2H),2.87(dt,J=13.3,6.9Hz,1H),2.24–2. 14(m,1H),1.88–1.77(m,1H),1.29(d,J=7.2Hz,3H),1.23(t,J=7.3Hz,3H). 13 C NMR (101MHz, CDCl3) δ174.9,174.8,61.1,33.6,33.6,33.3,32.4,18.7,18.5,14.1. 31 P NMR(162MHz,CDCl3)δ34.19.C6H 12 O4P - [M–H] - MS (ESI) m / z calculated value: 179.1, found value: 179.1.

[0119] (2-(Ethoxycarbonyl)-4-methylpentyl)phosphinic acid (3c)

[0120]

[0121] Chemical formula: C9H19O4P, exact molecular weight 222.1021, molar molecular weight 222.2208.

[0122] Light yellow viscous oil; yield 99%. Rf (DCM / MeOH / AcOH=7 / 0.8 / 0.4)=0.42. 1H NMR (400MHz, CDCl3) δ7.16 (d, 1 J P-H =564Hz,1H),4.15(q,J=7.1Hz,2H),2.82(ddt,J=18.1,12.5,6.4Hz,1H),2.18–2.04(m,1H),1.90–1.81(m,1H),1.6 2(dd,J=26.1,13.0,6.9Hz,2H),1.38(dd,J=13.0,6.7Hz,1H),1.26(t,J=7.1Hz,3H),0.90(dd,J=12.7,6.3Hz,6H). 13 C NMR (101MHz, CDCl3) δ174.8 (d, J = 6.0Hz), 61.0, 42.6 (d, J = 12.1Hz), 37.0, 31.6, (d, J = 94.9Hz), 25.7, 22.5, 22.1, 14.1. 31 P NMR(162MHz,CDCl3)δ35.38.C9H 18 O4P - [M–H] - MS (ESI) m / z calculated value: 221.1, found value: 221.1.

[0123] (2-Benzyl-3-ethoxy-3-oxypropyl)phosphinic acid (3d)

[0124]

[0125] Chemical formula: C12H17O4P, exact molecular weight: 256.0864, ​​molar molecular weight: 256.2378.

[0126] Light yellow viscous oil; yield 99%. Rf (DCM / MeOH / AcOH=7 / 0.8 / 0.4)=0.53. 1 H NMR (400MHz, CDCl3) δ7.29(t,J=7.2Hz,2H),7.24(d,J=7.1Hz,1H),7.18–7.15(m,2H),7.08(d, 1 J P-H =564Hz,1H),4.13(q,J=7.2Hz,2H),3.10–3.04(m,2H),2.91(dt,J=12.8,5.2H z,1H),2.12(td,J=14.6,8.8Hz,1H),1.90–1.80(m,1H),1.20(t,J=7.1Hz,3H). 13C NMR (151MHz, CDCl3) δ172.9, 136.8, 128.4, 127.8, 126.1, 60.3, 39.9, 38.4, 29.7 (d, J = 95.1Hz), 13.3. 31 P NMR (243MHz,CDCl3)δ34.58.C 12 H 16 O4P - [M–H] - MS (ESI) m / z calcd. 255.0, found 255.0.

[0127] (2-(Ethoxycarbonyl)-5-phenylpentyl)phosphinic acid (3e)

[0128]

[0129] Chemical formula: C14H21O4P, exact molecular weight: 284.1177, molar molecular weight: 284.2918.

[0130] Light yellow viscous oil; yield 99%. Rf (DCM / MeOH / AcOH=7 / 0.8 / 0.4)=0.58. 1 H NMR (400MHz, CDCl3) δ7.26-7.22(m,2H),7.17-7.11(m,3H),6.96(d, 1 J P-H =564Hz,1H),4.11(q,J=7.3Hz,2H),2.84–2.75(m,1H),2.58(app t,J=7.0Hz,2H),2.22–2.12(m,1H),1.81–1.56(m,5H),1.21(t,J=7.1Hz,3H). 13 C NMR (151MHz, CDCl3) δ175.4 (d, J = 6.0Hz), 162.6, 142.1, 128.3, 128.3, 128.3, 125.7, 60.4 ,39.8,36.5,35.6,34.5,33.8(d,J=10.1Hz),32.5(d,J=92.1Hz),31.4,29.7,28.7,14.2.C 14 H 20 O4P - [M–H] - MS (ESI) m / z calculated value: 283.1, found value: 283.1.

[0131] The general procedure for the synthesis of symmetrical phosphinic acids 4a-e is as follows:

[0132] In an oven-dried flask, a solution of phosphinic acid 3a-e (1.0 eq) in anhydrous DCM (2 ml DCM was used for 1 mmol of phosphinic acid) was added, followed by triethylamine (7.0 eq) and acrylate 2a-e (1.2 eq). The mixture was cooled to 0°C and purged with N2 for 15 min. Subsequently, TMSCl (7.0 eq) was added dropwise to the reaction mixture over 15 min. The temperature was slowly raised to room temperature, and the resulting clear solution was reacted under stirring. 31 P NMR monitoring is until the reaction is complete (reaction time is 48-72h). MeOH (relative to 1mmol phosphinic acid, use 1mL MeOH), and at room temperature continue to stir 30min. Volatiles are removed under vacuum to obtain a light yellow viscous oily crude product. The crude product is dissolved in ethyl acetate, and the resulting solution is washed three times with 1M HCl, washed with salt water, and then Na2SO4 is dried, and concentrated in vacuo, and the concentrated solution is purified by column chromatography, using DCM / MeOH / AcOH (volume ratio is 7 / 0.5 / 0.1-0.5) as eluent.

[0133] Bis(3-ethoxy-3-oxypropyl)phosphinic acid (4a)

[0134]

[0135] Chemical formula: C10H19O6P, exact molecular weight: 266.0919, molar molecular weight: 266.2298.

[0136] Yellow solid (yield 99%), mp: 58° C. Rf (DCM / MeOH / AcOH=7 / 0.5 / 0.5)=0.33. 1 H NMR (400MHz, CDCl3) δ4.12 (q, J = 7.2Hz, 4H), 2.63–2.56 (m, 4H), 2.02 (dt, J = 14.7, 8.1Hz, 4H), 1.23 (t, J = 7.2Hz, 6H). 13 C NMR (101MHz, CDCl3) δ172.1 (d, J = 16.0Hz), 61.0, 26.5 (d, J = 3.0Hz), 24.0 (d, J = 94.9Hz), 14.1. 31 P NMR (162MHz,CDCl3)δ55.73.C 10 H 19 O6P[M+H] + HRMS (ESI) m / z calculated value: 267.0919, found value: 267.0993.

[0137] Bis(3-ethoxy-2-methyl-3-oxypropyl)phosphinic acid (4b)

[0138]

[0139] Chemical formula: C12H23O6P, exact molecular weight: 294.1232, molar molecular weight: 294.2838.

[0140] Light yellow viscous oil (yield 96%); Rf (DCM / MeOH / AcOH=7 / 0.5 / 0.5)=0.45. 1 H NMR (600MHz, CDCl3) δ4.17–4.13(m,4H),2.93–2.82(m,2H),2.28(dddd,J=19.2,11.7 ,7.4,4.8Hz,2H),1.89–1.78(m,2H),1.35–1.30(m,6H),1.27(td,J=7.1,2.7Hz,6H). 13 C NMR (101MHz, CDCl3) δ175.3 (d, J = 9.1Hz), 61.49, 34.04 (d, J = 3.0Hz), 33.3 (d, J = 95.95Hz), 19.1, 18.9, 14.5. 31 P NMR (243MHz, CDCl3) δ55.86,55.73.C 12 H 23 O6P[M+H] + HRMS (ESI) m / z calculated value: 295.1232, found value: 295.1306.

[0141] Bis(2-(ethoxycarbonyl)-4-methylpentyl)phosphinic acid (4c)

[0142]

[0143] Chemical formula: C18H35O6P, precise molecular weight: 378.2171, molar molecular weight: 378.4458

[0144] Light yellow viscous oil (yield 98%); Rf (DCM / MeOH / AcOH=7 / 0.5 / 0.5)=0.6. 1H NMR (400MHz, CDCl3) δ4.11(qd,J=7.3,2.8Hz,4H),2.81–2.76(m,2H),2.12(qd,J=13.6,6.8Hz,2H),1.75(tdd,J=15.0,7.2,4.3Hz,1H) ,1.59(dd,J=13.7,5.2Hz,1H),1.54–1.49(m,1H),1.35(dt,J=13.0,6.7Hz,1H),1.23(t,J=7.2Hz,6H),0.87(dd,J=16.5,6.2Hz,12H). 13 C NMR (101MHz, CDl3) δ175.3 (d, J = 6.0Hz), 60.8, 43.4, 37.4 (d, J = 2.0Hz), 32.0 (d, J = 91.9Hz), 31.9 (d, J = 91.9Hz), 25.8, 22.8, 21.9, 14.1. 31 P NMR (162MHz, CDCl3) δ55.32,5522.C 18 H 35 O6PNa[M+Na] + HRMS (ESI) m / z calculated value 401.2069, found value 401.2060.

[0145] Bis(2-benzyl-3-ethoxy-3-oxypropyl)phosphinic acid (4d)

[0146]

[0147] Chemical formula: C24H31O6P, exact molecular weight: 446.1858, molar molecular weight: 446.4798.

[0148] Light yellow viscous oil (yield 92%); Rf (DCM / MeOH / AcOH=7 / 0.5 / 0.5)=0.82. 1 H NMR (600MHz, CDCl3) δ7.29–7.22(m,4H),7.22–7.17(m,2H),7.17–7.09(m,4H),4.08–3.96(m,4H),3.05(s,2H),2.94(app q,J=10.5Hz,4H),2.18–2.11(m,2H),1.81(td,J=13.9,6.5Hz,2H),1.10(td,J=7.2,2.7Hz,6H). 13C NMR (101MHz, CDCl3) δ 174.1 (d, J = 6.0Hz), 137.9, 129.2, 128.4, 126.7, 60.8, 41.0 (d, J = 7.0Hz), 39.7 (d, J = 11.1Hz), 31.1 (d, J = 93.9Hz), 14.0. 31 P NMR (162MHz, CDCl3) δ56.28,56.19.C 24 H 31 O6PNa[M+Na] + HRMS (ESI) m / z calculated value 469.1756, found value 469.1746.

[0149] Bis(2-(ethoxycarbonyl)-5-phenylpentyl)phosphinic acid(4e)

[0150]

[0151] Chemical formula: C28H39O6P, exact molecular weight: 502.2484, molar molecular weight: 502.5878.

[0152] Pale yellow oil (yield 94%); Rf (DCM / MeOH / AcOH=7 / 0.5 / 0.5)=0.91. 1 H NMR (400MHz, CDCl3) δ7.24(t,J=7.4Hz,4H),7.17–7.11(m,6H),4.11(q,J=7.3Hz,4H),2.80(ddt,J=12.3,8.1,4. 2Hz,2H),2.58(t,J=7.0Hz,4H),2.18(ddd,J=19.6,13.3,9.7Hz,2H),1.81–1.56(m,10H),1.21(t,J=7.1Hz,6H). 13 C NMR (151MHz, CDCl3) δ174.4 (d, J = 7.5Hz), 161.6, 141.1, 127.3, 127.3, 127.2, 124.7, 59.4, 38.8, 35.5, 34.6, 33.5, 32.9 (d, J = 16.6Hz), 32.8 (d, J = 10.6Hz), 31.5 (d, J = 90.1Hz), 28.7, 27.66, 13.2. 31 P NMR (162MHz, CDCl3) δ56.66,56.59.C 28 H 39 O6P[M+H] + HRMS (ESI) m / z calculated value: 503.2484, found value: 503.2554.

[0153] Ethyl 3-((adamantan-1-yloxy)(2-benzyl-3-ethoxy-3-oxypropyl)phosphoryl)-2-benzylpropanoate (5)

[0154]

[0155] Chemical formula: C34H45O6P, exact molecular weight: 580.2954, molar molecular weight: 580.7018.

[0156] Compound 4d (4.465 g, 10 mmol) and 1-adamantyl bromide (1.2 eq, 12 mmol, 2.58 g) were dissolved in CHCl3 (100 mL), and the solution was refluxed for 15 min. Silver oxide (1.2 eq, 12 mmol, 2.78 g) was added to the refluxed solution in five equal portions within 50 minutes. After the solution was refluxed for 5 h, or until the reflux reaction was complete, the solvent was removed under reduced pressure and the residue was suspended in ether. Silver bromide was removed by diatomite filtration. The filtrate was concentrated under reduced pressure, and further chromatographic purification was performed using DCM / i-PrOH (dichloromethane / isopropanol volume ratio) = 9.8 / 0.2 as eluent to obtain compound 5.

[0157] White solid (yield 92%); Rf (DCM / MeOH=9.7 / 0.3) 0.72. 1 H NMR (600MHz, CDCl3) δ7.21–7.17(m,4H),7.12(t,J=7.3Hz,2H),7.08(d,J=7.6Hz,4H),4.03–3.90(m,4H),2.95–2.85(m,4H),2.81–2.7 3(m,2H),2.17–2.04(m,2H),2.04–1.98(m,4H),1.86–1.78(m,6H),1.69(tt,J=14.0,3.8Hz,1H),1.50–1.46(m,6H),1.07–1.01(m,6H); 13 C NMR (101MHz, CDCl3) δ174.4,174.3,174.3,138.2,129.3,129.2,129.2,129.2,128.5,128.5,128.4,126.7,126.7,126.7,12 6.6,64.4,60.7,49.3,45.9,44.1,44.1,41.8,41.7,41.7,36.5,35.7,35.7,35.7,35.5,32.6,31.7,31.1,31.1,25.4,14.0; 31P NMR (162MHz, CDCl3) δ48.88, 48.64, 48.42.

[0158] 3-((Adamantane-1-yloxy)(2-carboxy-3-phenylpropyl)phosphoryl)-2-benzylpropanoic acid (6)

[0159]

[0160] Chemical formula: C30H37O6P, exact molecular weight: 524.2328, molar molecular weight: 524.5938.

[0161] To a solution of compound 5 (13 g, 22.39 mmol) in MeOH (18.6 mL) was added dropwise a 6 M aqueous LiOH solution (18.6 mL) to a final concentration of 3 M LiOH, and the mixture was stirred at room temperature for 24 h, the solvent was removed under reduced pressure, the residue was diluted with water, and acidified to pH 1 with 0.5 M HCl in an ice-water bath. The aqueous solution was extracted 3 times with AcOEt, the organic layer was washed with water and brine, then dried over Na2SO4, filtered and concentrated under reduced pressure, and purified by column chromatography (eluent: DCM / MeOH volume ratio = 9.5 / 0.5) to give compound 6.

[0162] Compound 6 is a white solid (yield 82%); Rf (DCM / MeOH=9.5 / 0.5) 0.35. 1 H NMR (400MHz, CDCl3) δ7.34–7.12(m,10H),3.3–3.0(m,3H),2.92(s,1H),2.7 9–2.58(m,2H),2.37–2.14(m,3H),2.10–1.96(m,3H),1.91(s,1H),1.76(app d,J=13.3Hz,5H),1.65(app s,3H),1.59–1.42(m,6H); 13 C NMR (101MHz, CDCl3) δ138.9,138.8,129.4,129.3,129.2,129.2,128.5,128. 4,126.5,126.4,53.5,45.3,44.0,44.0,44.0,36.1,35.6,35.6,31.1,30.7; 31 P NMR (162MHz, CDCl3) δ54.26, 53.21, 52.10.

[0163] The general steps for synthesizing compounds 8a-g are as follows:

[0164] Under stirring, DIPEA (4eq, 5.6mmol, 1.44g, 0.95mL) was added to a suspension of compound 6 (1.4mmol, 0.73g) in DCM (35mL), followed by amide 7a-g (2.2eq, 3.1mmol) and HOBt (2eq, 2.8mmol, 0.37g), followed by EDC·HCl (5.7eq, 8mmol, 2.13g) and another 5.6mmol (4eq) of DIPEA. The reaction mixture was stirred at room temperature for 12-24h (TLC was used to monitor the reaction until completion during the preparation of each compound). The reaction mixture was diluted with DCM (60mL) and washed with 1M HCl (3×5mL), saturated NH4HCO3 solution (3×1mL), 1M HCl (to pH 1) and brine (10mL) in sequence. The organic layer was dried over Na2SO4, concentrated under reduced pressure, and purified by column chromatography (using DCM / MeOH volume ratio = 9.8 / 0.2 to 9 / 1 as eluent) to give the desired product.

[0165] Adamantane-1-yl bis(3-((2-amino-2-oxoethyl)amino)-2-benzyl-3-oxopropyl)phosphinate (8a)

[0166]

[0167] Chemical formula: C34H45N4O6P, exact molecular weight: 636.31, molar molecular weight: 636.73.

[0168] Pale yellow oil (yield 76%); Rf (DCM / MeOH=9 / 1) 0.37. 1 H NMR(600MHz, CDCl3)δ8.18(s,1H),7.84(s,1H),7.47(s,1H),7.25–7.19(m,5H),7.18–7.08(m,6H),6.95(s,1H),6.73(s,1H), 6.46(s,1H),4.19–3.87(m,2H),3.68(s,1H),3.55–3.15(m,2H),3.06–2.79(m,4H),2.61–2.42(m,2H),2.14(s,2H),1.97(app d,J=33.4Hz,3H),1.86(s,1H),1.65–1.59(m,5H),1.50–1.36(m,7H); 13C NMR (101MHz, CDCl3) δ174.7,174.5,138.4,138.2,129.2,128.6,128.6,126.7,50 .3,44.4,44.4,44.3,44.2,44.2,43.0,40.2,35.6,35.5,35.5,31.1,31.0,31.0; 31 P NMR (162MHz, CDCl3) δ51.86, 50.82, 49.50.

[0169] Adamantane-1-yl bis(3-(((S)-1-amino-1-oxopropyl-2-yl)amino)-2-benzyl-3-oxopropyl)phosphinate (8b)

[0170]

[0171] Chemical formula: C36H49N4O6P, exact molecular weight: 664.34, molar molecular weight: 664.78.

[0172] Pale yellow oil (yield 83%); Rf (DCM / MeOH=9 / 1) 0.40, 0.46. 1 H NMR (400MHz, CDCl3) δ8.10–7.76(m,1H),7.67–7.40(m,2H),7.33–7.09(m,10H),7.00–6.69(m,2H),6.45–6.15( m,1H),4.43–4.23(m,2H),2.80–2.65(m,4H),2.82–2.63(m,2H),2.52–2.34(m,1H),2.24–2.14(m,1H),2.08(app d,J=10.4Hz,3H),1.93(app s,1H),1.87–1.70(m,6H),1.64–1.46(m,7H),1.34–1.26(m,3H),1.14(app q,J=7.7Hz,3H); 13C NMR (101MHz, CDCl3) δ176.4,176.1,175.8,175.5,175.5,175.4,175.3,174.6,174.0,173.6,173. 3,138.5,138.5,138.4,138.3,129.3,129.2,129.1,128.7,128.6,128.6,128.5,126.7,82.9,82.8 ,82.7,82.5,82.4,50.5,49.3,49.2,48.9,48.8,48.7,48.5,45.4,44.4,44.3,44.3,44.2,42.6,42.2,40.6,36.1,35.6,35.6,35.5,35.5,31.1,31.0,31.0,17.5,17.5,17.3,17.3,17.2,17.2,16.9; 31 P NMR (162MHz, CDCl3) δ51.38, 50.89, 50.67, 50.22.

[0173] Adamantane-1-yl bis(3-(((S)-1-amino-3-methyl-1-oxobutan-2-yl)amino)-2-benzyl-3-oxopropyl)phosphinate (8c)

[0174]

[0175] Chemical formula: C40H57N4O6P, exact molecular weight: 720.40, molar molecular weight: 720.89.

[0176] Pale yellow oil (yield 82%); Rf (DCM / MeOH=9 / 1) 0.51, 0.54. 1 H NMR (600MHz, CDCl3) δ7.78 (s, 1H), 7.35 (t, J = 7.6Hz, 1H), 7.29–7.09 (m, 11H), 7.00 (d, J = 7.2Hz, 1H), 6. 87–6.41(m,2H),4.41–4.17(m,2H),3.23–2.92(m,4H),2.79–2.56(m,2H),2.50–2.25(m,1H),2.13(app q,J=6.8Hz,2H),2.09–2.03(m,3H),1.92(app d,J=11.1Hz,1H),1.88–1.74(m,6H),1.67–1.45(m,7H),0.98–0.84(m,6H),0.84–0.72(m,5H),0.69(d,J=7.0Hz,1H),0.59(d,J=6.9Hz,1H;13 C NMR (101MHz, CDCl3) δ175.1,174.5,174.1,138.6,138.6,138.4,129.3,129.2,129.2,129.2,129 .1,128.8,128.6,128.6,128.5,128.5,126.7,126.6,126.6,44.2,35.6,31.0,19.4,19.2,19.1; 31 P NMR (162MHz, CDCl3) δ52.02, 51.68, 51.15, 50.80.

[0177] Adamantane-1-yl bis(3-(((S)-1-amino-4-methyl-1-oxopentan-2-yl)amino)-2-benzyl-3-oxopropyl)phosphinate (8d)

[0178]

[0179] Chemical formula: C42H61N4O6P, exact molecular weight: 748.43, molar molecular weight: 748.95.

[0180] Light yellow oil (yield 85%), Rf (DCM / MeOH=9 / 1) 0.45, 0.58. 1 H NMR (400MHz, CDCl3) δ8.10–7.87(m,1H),7.68–7.54(m,1H),7.37–7.14(m,10H),7.09(d,J=7.5Hz,1H),7.01–6. 80(m,1H),6.76–6.56(m,1H),6.41–6.22(m,1H),4.48–4.26(m,2H),3.22–2.91(m,4H),2.80–2.63(m,2H),2.41( td,J=21.1,18.7,10.8Hz,1H),2.28–2.16(m,1H),2.12–2.04(m,3H),1.99–1.85(m,3H),1.85–1.72(m,4H),1.5 5(d,J=10.9Hz,11H),1.42–1.20(m,2H),0.92–0.82(m,8H),0.76(dt,J=19.4,6.0Hz,3H),0.67(d,J=6.4Hz,1H); 13C NMR (101MHz, CDCl3) δ176.3,175.9,175.7,174.2,173.8,173.7,138.7,138.6,138.4,138.3,129.4,129.3,129.2,129.2, 129.1,128.7,128.6,128.5,126.7,126.7,126.6,44.3,44.3,35.6,31.1,31.1,31.0,31.0,24.7,23.5,23.5,23.1,21.8; 31 P NMR (162MHz, CDCl3) δ51.67,51.57,50.96,50.71.

[0181] Adamantane-1-yl bis(3-(((S)-1-amino-1-oxo-3-phenylpropan-2-yl)amino)-2-benzyl-3-oxopropyl)phosphinate (8e)

[0182]

[0183] Chemical formula: C48H57N4O6P, exact molecular weight: 816.4016, molar molecular weight: 816.9798.

[0184] Light yellow oil (yield 79%); Rf (DCM / MeOH=9 / 1) 0.68, 0.72. 1 H NMR (600MHz, CDCl3) δ7.93–7.65(m,1H),7.60–7.39(m,1H),7.32–6.99(m,20H),6.96–6.80(m,2H), 6.77–6.39(m,2H),4.79–4.67(m,1H),4.64–4.47(m,1H),3.42–3.36(m,1H),3.32–3.25(m,1H),3.20 –3.07(m,2H),3.03–2.96(m,1H),2.95–2.88(m,1H),2.88–2.75(m,3H),2.68(d,J=6.8Hz,1H),2.64 –2.56(m,1H),2.55–2.44(m,1H),2.41–2.31(m,1H),2.26–2.10(m,1H),2.10–2.00(m,2H),1.96(app d,J=20.1Hz,1H),1.90–1.80(m,3H),1.70–1.57(m,3H),1.57–1.45(m,4H),1.41(t,J=14.2Hz,1H),1.34–1.24(m,1H); 13C NMR (101MHz, CDCl3) δ175.1,174.4,173.9,173.8,138.5,137.7,129.5,129 .4,129.4,129.3,129.3,129.2,129.2,129.1,129.0,128.7,128.7,128.6, 128.6,128.6,128.5,128.5,128.4,127.0,126.9,126.8,126.7,126.7,126.6,50.4,45.3,44.3,44.2,44.2,44.2,36.1,35.6,35.4,31.1,31.1,31.0; 31 P NMR (162MHz, CDCl3) δ51.51, 51.35, 51.00, 50.53.

[0185] Adamantane-1-yl bis(2-benzyl-3-((S)-2-carbamoylpyrrolidin-1-yl)-3-oxypropyl)phosphinate (8f)

[0186]

[0187] Chemical formula: C40H53N4O6P, exact molecular weight: 716.37, molar molecular weight: 716.86.

[0188] Pale yellow oil (yield 68%); Rf (DCM / MeOH=9 / 1) 0.72, 0.75. 1 H NMR (400MHz, CDCl3) δ7.89–7.63(m,1H),7.50–7.42(m,1H),7.28–7.10(m,10H),6.53–6.13( m,1H),5.89–5.59(m,1H),4.58–4.27(m,2H),3.67–3.47(m,2H),3.46–3.26(m,2H),3.19–3. 01(m,2H),2.94–2.82(m,2H),2.80–2.73(m,1H),2.71–2.54(m,3H),2.51–2.39(m,1H),2.19 –2.01(m,6H),1.98–1.91(m,2H),1.90–1.82(m,3H),1.80–1.76(m,2H),1.73–1.38(m,11H); 13C NMR (101MHz, CDCl3) δ175.1,175.0,174.3,173.7,173.7,173.1,172.9,172.8,172.6,138.3,138.3,138.0 ,137.8,129.3,129.2,129.2,129.1,129.1,129.0,129.0,128.8,128.7,128.7,128.7,128.6,128.6,128.5 ,128.5,128.4,128.4,127.1,127.0,127.0,126.9,126.9,83.2,60.4,60.2,60.2,59.9,59.7,47.3,46.8,46.6,46.5,44.5,44.3,44.3,40.8,40.8,35.6,35.6,31.0,31.0,31.0,29.3,29.1,27.8,24.8,24.7,23.8; 31 P NMR (162MHz, CDCl3) δ57.40,56.59,55.99,55.26,51.33,50.72,50.59,50.25,50.07,49.72,49.45,49.17,49.02.

[0189] Adamantane-1-yl bis(3-(((S)-1-amino-3-(1H-indol-3-yl)-1-oxopropyl-2-yl)amino)-2-benzyl-3-oxopropyl)phosphinate (8 g)

[0190]

[0191] Chemical formula: C52H59N6O6P, exact molecular weight: 894.42, molar molecular weight: 895.05.

[0192] Pale yellow oil (yield 66%); Rf (DCM / MeOH=9 / 1) 0.42. 1H NMR (600MHz, CDCl3) δ9.43–8.69(m,2H),7.56–7.52(m,1H),7.33–6.95(m,20H),6.82–6.68(m,4H),6.32(s,1H),4.71(app s,1H),4.55(app s,1H),3.27–3.07(m,3H),2.93(app s,1H),2.79(app s,2H),2.61–2.31(m,5H),1.94-1.93(m,3H),1.81–1.70(m,5H),1.45–1.34(m,8H),1.27(t,J=9.5Hz,2H); 13 C NMR (101MHz, CDCl3) δ175.3,174.9,173.9,173.7,138.6,138.2,136.3,136.2,129.3,129.2,129.1,128.7,127.8,127.7,127.5,12 6.8,124.3,121.9,119.3,118.6,111.6,110.1,50.5,44.2,44.2,44.1,44.1,44.0,44.0,43.9,35.5,35.4,31.1,31.0,30.9,30.9; 31 P NMR (162MHz, CDCl3) δ51.25, 50.41, 50.11.

[0193] General procedure for the synthesis of compounds 9a-g:

[0194] The phosphine peptide (phosphinopeptide) derivative 8a-g (1.5mmol) of P-Ad protection is processed with the mixture of 10mL DCM / TFA / TIS / H2O=50 / 50 / 0.1 / 0.1, and at room temperature stirs for 3h.After reaction is completed, monitor by TLC, remove solvent under reduced pressure.The product is dissolved in minimum DCM, and add the mixture of ether / hexane volume ratio=1 / 1 to precipitate the product, filter it and wash with ether / hexane volume ratio=1 / 1.

[0195] Bis(3-((2-amino-2-oxoethyl)amino)-2-benzyl-3-oxopropyl)phosphinic acid (PAC-Phe-Gly)(9a)

[0196]

[0197] Chemical formula: C24H31N4O6P, exact molecular weight: 502.20, molar molecular weight: 502.51

[0198] Pale yellow oil (yield 85%); Rf (DCM / MeOH / AcOH=7 / 0.5 / 0.5) 0.16. 1 H NMR(600MHz,DMSO)δ8.34–8.24(m,2H),7.56(app d,J=5.4Hz,1H),7.28–7.24(m,5H),7.20–7.14(m,7H),6.98–6.92(m,1H),3.73–3.67(m,2H),3.33–3.25 (m,1H),2.89–2.80(m,4H),2.65–2.59(m,2H),2.21–2.19(m,2H),1.99–1.95(m,2H),1.90–1.88(m,2H); 13 C NMR(151MHz,DMSO)δ174.1,174.1,174.0,174.0,172.1,172.0,172.0,139.5,139.4,129.5,128 .6,128.6,126.7,126.7,87.9,66.4,45.7,42.7,40.7,36.4,35.6,30.9,30.5,29.3,18.3,12.5; 31 P NMR (243MHz, DMSO) δ46.60,46.56; C 24 H 30 N4O6P - [MH] - MS (ESI) m / z calculated value = 501.1, found value 501.1; C 24 H 31 N4O6P[M+H] + HRMS (ESI) m / z calculated value 503.2053, found value 503.2045; HPLC: DAD1A / B, Sig=220 / 254: rt 12.374, 14.780.

[0199] Bis(3-(((S)-1-amino-1-oxopropyl-2-yl)amino)-2-benzyl-3-oxopropyl)phosphinic acid (PAC-Phe-Ala)(9b)

[0200]

[0201] Chemical formula: C26H35N4O6P, exact molecular weight: 530.23, molar molecular weight: 530.56.

[0202] Pale yellow oil (yield 85%); Rf (DCM / MeOH / AcOH=7 / 0.5 / 0.5) 0.17. 1H NMR(600MHz,DMSO-d6)δ8.11(d,J=7.6Hz,1H),8.03–7.96(m,2H),7.83(d,J=5.4Hz ,1H),7.56(s,1H),7.30–7.22(m,4H),7.21–7.11(m,6H),6.92–6.85(m,1H),4.16– 3.97(m,2H),2.90–2.80(m,3H),2.77–2.67(m,2H),2.63(td,J=12.5,8.7Hz,1H),2 .19(s,2H),1.93–1.85(m,1H),1.23(s,2H),1.21–1.15(m,2H),0.97–0.86(m,6H); 13 C NMR (151MHz, DMSO) δ173.4,173.3,173.0,172.9,171.5,127.7,126.7,86.1,64.7,43.9,38.9,34.6,33.8,29.2,28.8,16.5,10.8; 31 P NMR (243MHz, DMSO) δ46.96, 46.89, 46.81; C 26 H 34 N4O6P - [MH] - MS (ESI) m / z calculated value = 529.3, found value 529.3; C 26 H 35 N4O6P[M+H] + HRMS (ESI) m / z calculated value 531.2366, found value 531.2369; HPLC: DAD1A / B, Sig=220 / 254: rt 12.070, 14.255, 21.342.

[0203] Bis(3-(((S)-1-amino-3-methyl-1-oxobutan-2-yl)amino)-2-benzyl-3-oxopropyl)phosphinic acid (9c)

[0204]

[0205] Chemical formula: C30H43N4O6P, exact molecular weight: 586.29, molar molecular weight: 586.67.

[0206] White solid (yield 82%); Rf (DCM / MeOH / AcOH=7 / 0.5 / 0.5) 0.20. 1H NMR(600MHz,DMSO-d6)δ8.10(d,J=8.9Hz,1H),8.00–7.87(m,1H),7.75–7.68(m,1H),7.28–7.13(m,11H),6.97–6.90(m,1H) ,6.78(s,1H),4.06(ddd,J=26.0,8.9,6.5Hz,1H),3.92(ddd,J=45.4,8.7,4.5Hz,1H),3.22(d,J=11.3Hz,1H),3.07–3.01(m, 1H),2.96–2.86(m,1H),2.78–2.67(m,3H),2.19(s,1H),2.04–1.94(m,3H),1.92–1.86(m,1H),1.59–1.53(m,3H),0.99(d,J =7.0Hz,1H),0.85(ddd,J=19.2,6.8,3.7Hz,5H),0.64(dd,J=21.9,6.9Hz,3H),0.49(d,J=6.8Hz,1H),0.36(d,J=6.8Hz,1H); 31 P NMR (243MHz, DMSO) δ47.11, 47.03, 46.84, 46.76; 13 C NMR(151MHz,DMSO)δ174.1,174.1,174.0,174.0,172.0,172.0,139.5,139.4,129.5,129.4,128.6, 128.6,128.6,126.7,87.9,66.4,45.7,42.7,41.3,40.7,36.4,35.6,30.9,30.5,29.3,18.3,12.5; 31 P NMR (243MHz, DMSO) δ47.03,46.76; C 30 H 42 N4O6P - [MH] - MS (ESI) m / z calculated value = 585.3, found value 585.3; C 30 H 43 N4O6P[M+H] + HRMS (ESI) m / z calculated value 587.2992, found value 587.2993; HPLC: DAD1A / B, Sig=220 / 254: 16.106, 24.295, 32.821.

[0207] Bis(3-(((S)-1-amino-4-methyl-1-oxopentan-2-yl)amino)-2-benzyl-3-oxopropyl)phosphinic acid (9d)

[0208]

[0209] Chemical formula: C32H47N4O6P, exact molecular weight: 614.32, molar molecular weight: 614.72

[0210] White solid (yield 80%); Rf (DCM / MeOH / AcOH=7 / 0.5 / 0.5) 0.22. 1 H NMR(600MHz,DMSO-d6)δ8.19(d,J=8.1Hz,1H),8.06–8.01(m,1H),7.92(d,J=8.0Hz,1H),7.68(s,1H) ,7.30–7.10(m,11H),6.93–6.87(m,1H),6.77(s,1H),4.20–4.07(m,1H),3.97–3.84(m,1H),3.00–2. 85(m,3H),2.78–2.64(m,3H),2.15–2.11(m,2H)),2.04–1.95(m,1H),1.67–1.61(m,2H),1.56–1.52( m,2H),1.50–1.44(m,1H),1.43–1.37(m,1H),1.28–1.17(m,1H),0.99(appd,J=7.1Hz,2H),0.88(app d,J=6.6Hz,1H),0.84(app t,J=7.4Hz,2H),0.79(app d,J=6.4Hz,1H),0.68(dd,J=26.3,6.6Hz,3H),0.55(dd,J=32.1,6.4Hz,3H); 13 C NMR (151MHz, DMSO) δ175.3,175.2,174.7,174.7,139.5,139.5,139.3,139.2,129.6,129.5,129.4,129.4,128.6,128.6,128.5,128. 4,51.7,51.6,51.4,51.3,45.7,40.7,36.4,35.6,30.9,30.5,24.6,24.5,23.9,23.8,23.7,23.6,22.0,21.9,21.4,21.3,18.3,12.5; 31 P NMR (243MHz, DMSO) δ47.07,46.95; C 32 H 46N4O6P - [MH] - MS (ESI) m / z calculated value = 613.3, found value 613.3; C 32 H 47 N4O6P[M+H] + HRMS (ESI) m / z calculated value: 615.3305, found value: 615.3304; HPLC DAD1A / B, Sig=220 / 254: 27.4, 38.8, 52.2.

[0211] Bis(3-(((S)-1-amino-1-oxo-3-phenylpropan-2-yl)amino)-2-benzyl-3-oxopropyl)phosphinic acid (9e)

[0212]

[0213] Chemical formula: C38H43N4O6P, exact molecular weight: 682.29, molar molecular weight: 682.76.

[0214] White solid (yield 80%); Rf (DCM / MeOH / AcOH=7 / 0.5 / 0.5) 0.24. 1 H NMR (600MHz, DMSO-d6) δ8.28(ddd,J=54.8,35.5,8.5Hz,2H),7.39(d,J=7.2Hz,1H),7.31(d,J=9.6Hz,1H),7.24–7.10(m,15H),7.08–6.94(m,5H ),4.39–4.27(m,2H),3.12–3.04(m,2H),2.93–2.75(m,3),2.74–2.62(m ,3H),2.36–2.27(m,1H),2.13–1.98(m,1H),1.93–1.71(m,1H),1.59(app d,J=19.2Hz,2H); 13 C NMR (151MHz, DMSO) δ174.1,174.0,173.6,173.6,139.7,139.7,139.3,139. 2,139.1,139.0,138.9,138.9,129.7,129.7,129.6,129.6,129.5,129.5,12 9.5,129.4,128.6,128.6,128.6,128.5,128.5,128.5,128.4,126.6,126.6,126.6,126.5,126.5,47.7,45.7,40.7,36.4,35.6,30.9,30.5,18.3,12.6; 31P NMR (243MHz, DMSO) δ47.31, 47.17, 46.75; C 38 H 42 N4O6P - [MH] - MS (ESI) m / z calculated value = 681.8, found value 681.8.

[0215] Bis(2-benzyl-3-((S)-2-carbamoylpyrrolidin-1-yl)-3-oxypropyl)phosphinic acid (9f)

[0216]

[0217] Chemical formula: C30H39N4O6P, exact molecular weight: 582.26, molar molecular weight: 582.64.

[0218] Pale yellow oil (yield 78%); Rf (DCM / MeOH / AcOH=7 / 1 / 0.5) 0.22. 1 H NMR(600MHz,DMSO-d6)δ7.85–7.78(m,1H),7.52(s,1H),7.32–7.11(m,10H),6.95–6.92 (m,1H),6.86–6.80(m,1H),4.08–3.98(m,1H),3.52–3.42(m,1H),3.41–3.30(m,1H),3.0 8–2.93(m,2H),2.79–2.67(m,2H),2.64–2.60(m,1H),2.21–2.12(m,2H),2.07–1.99(m,1 H),1.93–1.86(m,1H),1.82–1.75(m,3H),1.71(ddd,J=14.7,11.9,2.7Hz,1H),1.64(app d,J=3.0Hz,1H),1.62–1.41(m,6H),0.99(app d,J=7.0Hz,2H); 13C NMR (151MHz, DMSO) δ174.4,174.3,174.2,172.9,172.9,172.7,172.7,158.9,158 .7,139.2,129.8,129.7,129.4,129.4,129.3,128.8,128.8,128.7,128.7,128.6 ,128.6,128.6,126.9,126.8,117.6,115.6,87.9,60.2,60.2,60.0,47.4,46.8,46.7,45.7,36.4,35.6,30.9,30.5,29.6,29.5,29.5,24.6,24.0,23.9,18.3,12.5; 31 P NMR (243MHz, DMSO) δ47.32, 46.55, 46.35, 46.24, 46.22; C 30 H 38 N4O6P - [MH] - MS (ESI) m / z calculated value = 581.3, found value 581.3; C 30 H 39 N4O6P[M+H] + HRMS (ESI) m / z calculated value 583.2679, found value 583.2678; HPLC: DAD1A / B, Sig=220 / 254: 16.740, 20.416, 25.200.

[0219] Bis(3-(((S)-1-amino-3-(1H-indol-3-yl)-1-oxopropyl-2-yl)amino)-2-benzyl-3-oxopropyl)phosphinic acid (9 g)

[0220]

[0221] Chemical formula: C42H45N6O6P, exact molecular weight: 760.31, molar molecular weight: 760.83.

[0222] Green solid (yield 78%); Rf (DCM / MeOH / AcOH=7 / 1 / 0.5) 0.13. 1H NMR(600MHz,DMSO-d6)δ8.37–7.95(m,2H),7.78–7.45(m,3H),7.40–7.29(m,2H),7.28–7.07(m,10H),7.07–7.01(m,3H),7.00– 6.91(m,5H),6.91–6.68(m,4H),4.51–4.32(m,1H),3.58–3.38(m,1H),3.02–2.61(m,5H),2.14–2.03(m,6H),1.92–1.85(m,3H); 13 C NMR (151MHz, DMSO) δ174.6,174.5,174.1,173.8,173.7,173.5,159.2,159. 0,158.7,158.5,136.6,129.7,129.5,129.5,129.0,128.5,127.7,126.6,1 26.5,124.0,121.2,119.1,118.9,118.6,117.2,115.2,113.3,111.7,111.1,110.9,55.5,49.1,43.9,42.1,36.7,29.0,28.9,28.6,28.6,18.3,12.6; 31 P NMR (243MHz, DMSO) δ47.50,47.47,47.46,47.38,47.33,47.22,47.04,46.96,46.85,46.81; C 42 H 44 N4O6P - [MH] - MS (ESI) m / z calculated value 760.3, found value 760.3; C 42 H 45 N4O6P[M+H] + HRMS (ESI) m / z calculated value 761.3210, found value 761.3207; HPLC: DAD1A / B, Sig=220 / 254: 35.664, 39.374, 45.107.

[0223] In vitro evaluation of HIV-1 inhibitory activity:

[0224] Evaluation Methodology:

[0225] Use the Fluorescent HIV-1 Protease Assay Kit ( 520 HIV protease assay kit AS-71147, AnaSpec Inc., USA), according to the manufacturer's recommended protocol, the inhibitory effect of the compound on HIV-1 wild-type protease was evaluated. Darunavir, an FDA-approved HIV-1 protease inhibitor, was used as a positive control. In addition, 0.01% (v / v) DMSO / H2O was used as a negative control. Darunavir was purchased from MedChemExpress (HY-17040, New Jersey, USA). The test compound was dissolved in DMSO and further diluted to different concentrations with the assay buffer in the kit. Varioskan TM The fluorescence was measured at 490 nm (excitation) and 520 nm (emission) in kinetic mode at 37° C. for 90 min using a LUX multimode microplate reader (Thermo Fisher Scientific Inc. USA). The raw data obtained were then normalized to the control, with 0.01% DMSO set as 0% inhibitory activity. IC was calculated using GraphPad Prism version 9.5.0 (GraphPad Software, San Diego, California, USA) by fitting the data to the four-parameter log(inhibitor) relative to the reaction equation. 50 value.

[0226] Test results:

[0227] like Figure 1 As shown in (A), among all the tested compounds, darunavir exhibited the highest level of enzyme inhibition, reaching almost complete inhibition within the three selected concentration ranges. Notably, PAC-Phe-Val (9c) showed a significant reduction in enzyme activity compared to the other PACs tested, indicating its potential as a potent inhibitor. At both 1 μM and 100 nM wavelengths, PAC-Phe-Val showed significant inhibition comparable to darunavir, suggesting that it may work through a similar mechanism of action.

[0228] In contrast, PAC-Phe-Leu (9d) showed moderate levels of enzyme inhibition, which, while promising, was less potent than PAC-Phe-Val and darunavir. On the other hand, PAC-Phe-Ala (9b) and PAC-Phe-Phe (9e) produced only weak inhibition, indicating limited potency against HIV-1 protease. Importantly, PAC-Phe-Gly (9a) and PAC-Phe-Pro (9f) did not exhibit any significant inhibition at any concentration tested, highlighting the need for further exploration of structural features that contribute to inhibitory activity.

[0229] Given the encouraging results observed for PAC-Phe-Val, we determined the IC 50 The inhibitory potency was further characterized by the measured IC 50 The value was 33.10 nM (95% CI: 22.18-51.01 nM). This result indicates high potency against wild-type HIV-1 protease, suggesting that PAC-Phe-Val can serve as a promising lead compound for further development.

[0230] Furthermore, PAC-Phe-Val was resolved, isolating the mixture into its potential isomers: SRSS, SSSS, and SRRS, identifying a variant with significant inhibitory activity down to 1 nM. This remarkable potency underscores the therapeutic potential of this isomer and warrants further investigation of its binding interactions with HIV-1 protease. To elucidate its mode of action, docking and computational studies were employed to analyze these interactions in detail.

[0231] The isomers of PAC-Phe-Val(9c) are as follows:

[0232]

[0233] Compound 9c showed particularly high inhibitory potency against HIV-1 protease with an IC50 value of 1 nM, suggesting potential for the development of anti-HIV therapeutics.

[0234] Thus, the present invention identifies a highly potent PAC-Phe-Val isomer, which not only highlights its potential for therapeutic applications, but also facilitates more in-depth studies on its mechanism of action and structural optimization, thereby enhancing its potency and selectivity against HIV-1 protease. Future studies should focus on evaluating the stability, pharmacokinetics, and possible resistance of this compound compared to existing inhibitors, ultimately paving the way for the development of new anti-HIV therapies.

[0235] Specific operations and methods for experimental testing on proliferation and activation of mouse T cells and proliferation and activation of human T cells;

[0236] The present invention has conducted preliminary experiments, indicating that compounds 9a and 9g showed reduced proliferation and activation of human T cells at a concentration of 100uM; however, only significant results were observed for compound 9g. Compounds 9a, 9b, 9e and 9g acted on mouse cells at a concentration of 75uM. Preliminary experiments showed an effect on T cell viability and proliferation after 4 days of stimulation with phosphinate derivatives (9a-9g) at a concentration of 75μM. FVD-660 dye and flow cytometry were used to evaluate the effect of phosphinate derivatives on T cell viability (such as Figure 2AAll derivative compounds did not show any cytotoxic effect on T-cell viability at this concentration compared to the DMSO control. The effect of phosphinate derivatives on T-cell proliferation was measured by CFSE loss after 4 days of stimulation (e.g. Figure 2B Compared to the DMSO control, compounds 1 (9g), 4 (9e), 5 (9b) and 7 (9a) induced a decrease in T cell proliferation, whereas compounds 2 (9d) and 3 (9f) showed no effect on T cell proliferation.

[0237] The effects of the above compounds on T cell proliferation and activation indicate that these compounds have potential immunomodulatory effects.

[0238] Further experiments were performed to evaluate the effect on T cell proliferation, as follows:

[0239] Compounds 9a-9g were dissolved in DMSO (100 mM concentration).

[0240] Cells: Animal research involving animal studies will be conducted at the Cam-Su-GRC, Soochow University (under agreement with XJTU). Splenocytes will be isolated from the spleens of normal C57BL / 6 mice.

[0241] Cell staining and activation: Splenocytes were cultured in Dulbecco's modified Eagle's medium (DMEM) supplemented with 10% fetal bovine serum and 1% antibiotics. Splenocytes were stained with carboxyfluorescein diacetate succinimidyl ester (CFSE) and then stimulated with a rapid-acting T cell activation kit (mouse anti-CD3 / CD28 antibody, from Cell Signaling Technology).

[0242] Cell treatment: Stained and activated T cells will be cultured for 3-4 days in the presence of seven compounds at different concentrations and an equal amount of DMSO (as a control). T cells were treated with seven compounds at different concentrations in 96-well plates to determine non-cytotoxic concentrations. As previously described, the effect of non-cytotoxic concentrations on the proliferation of activated T cells was assessed using flow cytometry in a CFSE dilution assay (Meyiah et al., Effect of Boswellic acids on T cell proliferation and activation. Int Immunopharmacol, 2023.122: p.110668).

[0243] Flow cytometric analysis: T cell proliferation was analyzed using a flow cytometer (BD FACSCelesta, available from our department). After culturing cells in the presence of seven compounds and DMSO control, cells were stained with fixable viability dye (FVD) (eBioscience) to measure cell viability and exclude dead cells, and T cell proliferation was assessed by CFSE dilution assay.

[0244] The applicant declares that the present invention uses the above-mentioned embodiments to illustrate the symmetrical phosphinic acid compounds, symmetrical phosphinic acid amino acid derivatives, and the preparation methods and applications thereof, but the present invention is not limited to the above-mentioned embodiments, that is, it does not mean that the present invention must rely on the above-mentioned embodiments to be implemented. Those skilled in the art should understand that any improvement of the present invention, equivalent replacement of the raw materials selected by the present invention, addition of auxiliary components, selection of specific methods, etc., all fall within the protection scope and disclosure scope of the present invention.

Claims

1. A symmetrical phosphinic acid compound, characterized in that: The symmetrical phosphinic acid compound has a structure as shown in the following formula C: Wherein R is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C30 aryl, and Et represents ethyl; Preferably, in formula C, R is selected from hydrogen, methyl, sec-butyl, isopropyl, benzyl or Preferably, the symmetrical phosphinic acid compound is any one of the following compounds 4a-4e:

2. The method for preparing a symmetrical phosphinic acid compound according to claim 1, characterized in that: The preparation method comprises the following steps: (1) ammonium phosphinate reacts with the acrylic acid ester compound of formula A to obtain a compound of formula B, and the reaction formula is as follows: (2) The compound represented by formula B reacts with the acrylic acid ester compound represented by formula A to obtain the compound represented by formula C. The reaction formula is as follows: Preferably, the molar ratio of the ammonium phosphinate in step (1) to the acrylate compound of formula A is 5:2; Preferably, the reaction in step (1) is carried out in the presence of hexamethyldisilazane (HMDS); Preferably, the molar ratio of hexamethyldisilazane to ammonium phosphinate is 4:2.5; Preferably, the reaction in step (1) is carried out in a solvent selected from dichloromethane and / or chloroform; Preferably, the reaction in step (1) is to mix ammonium phosphinate and hexamethyldisilazane for reaction, and then dropwise add an acrylic ester compound for reaction to obtain a compound represented by formula B; Preferably, the mixed reaction of ammonium phosphinate and hexamethyldisilazane is carried out at a temperature of 110° C. and the reaction time is 1 h; Preferably, after the mixed reaction of the ammonium phosphinate and hexamethyldisilazane is completed, the reaction mixture is cooled to 0° C., a solvent is added, and then a solution of an acrylic ester compound is added dropwise to react to obtain a compound represented by formula B; Preferably, the solvent is dichloromethane and / or chloroform; Preferably, the solution of the acrylate compound is a dichloromethane or chloroform solution of the acrylate compound; Preferably, the reaction after adding the acrylic acid ester compound is carried out at room temperature, and the reaction time is 24-48 hours; Preferably, the reaction in step (1) is carried out under nitrogen protection; Preferably, the molar ratio of the compound represented by formula B in step (2) to the acrylate compound represented by formula A is 1:1.2; Preferably, the reaction in step (2) is carried out in the presence of an alkaline substance; Preferably, the alkaline substance is selected from triethylamine; Preferably, the reaction in step (2) is carried out in a solvent selected from dichloromethane and / or chloroform; Preferably, the reaction in step (2) is carried out in the presence of 2,4,6-trimethylbenzenesulfonyl chloride; Preferably, the molar ratio of the 2,4,6-trimethylbenzenesulfonyl chloride to the compound represented by formula B is 7:1; Preferably, the reaction in step (2) is carried out at room temperature for 48-72 hours.

3. A symmetrical phosphinic acid compound, characterized in that: The symmetrical phosphinic acid compound has a structure as shown in the following formula D: Wherein R is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C30 aryl, and Et represents ethyl; Preferably, in formula D, R is selected from hydrogen, methyl, sec-butyl, isopropyl, benzyl or 4. The method for preparing a symmetrical phosphinic acid compound according to claim 3, characterized in that: The preparation method comprises the following steps: The compound represented by formula C reacts with 1-bromoadamantane to obtain the compound represented by formula D. The reaction formula is as follows: Preferably, the molar ratio of the compound represented by formula C to 1-bromoadamantane is 1:1.2; Preferably, the reaction of the compound represented by formula C with 1-bromoadamantane is carried out in a solvent selected from chloroform, Preferably, the reaction of the compound represented by formula C and 1-bromoadamantane is carried out in the presence of a catalyst; Preferably, the catalyst is selected from silver oxide. Preferably, the molar ratio of the catalyst to the compound represented by formula C is 1.2:1; Preferably, the specific operation of the reaction of the compound represented by formula C and 1-bromoadamantane is: dissolving the compound represented by formula C and 1-bromoadamantane in a solvent, refluxing the solution, and then adding a catalyst to the refluxing solution, and continuing the reflux reaction to obtain the compound represented by formula D; Preferably, the solution is refluxed for 10-30 min before adding the catalyst; Preferably, the reflux reaction is continued for 5-12 hours after the catalyst is added.

5. A symmetrical phosphinic acid compound, characterized in that: The symmetrical phosphinic acid compound has a structure shown in the following formula E: Wherein, R is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C30 aryl; Preferably, in formula E, R is selected from hydrogen, methyl, sec-butyl, isopropyl, benzyl or 6. The method for preparing a symmetrical phosphinic acid compound according to claim 5, characterized in that: The preparation method comprises the following steps: The compound represented by formula D is hydrolyzed to obtain the compound represented by formula E, and the reaction formula is as follows: Preferably, the hydrolysis reaction is carried out in a solvent, and the solvent is selected from methanol. Preferably, the hydrolysis reaction is carried out in the presence of an alkaline substance; Preferably, the alkaline substance is selected from lithium hydroxide. Preferably, the hydrolysis reaction is carried out at room temperature, and the hydrolysis reaction time is 12-24 hours.

7. A symmetrical phosphinic acid amino acid derivative, characterized in that: The symmetrical phosphinic acid amino acid derivative has a structure shown in the following formula H: wherein R is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C30 aryl, and R' is selected from amino acid side chains; Preferably, in formula H, R is selected from hydrogen, methyl, sec-butyl, isopropyl, benzyl or Preferably, R' is selected from the side chain of any one of the 20 natural amino acids; Preferably, R' is selected from the group consisting of a glycine side chain, an alanine side chain, a valine side chain, a leucine side chain, a phenylalanine side chain or a proline side chain; Preferably, the symmetrical phosphinic acid amino acid derivative is selected from any one of the following compounds 8a-8g:

8. The method for preparing a symmetrical phosphinic acid amino acid derivative according to claim 7, characterized in that: The preparation method comprises the following steps: The compound represented by formula E reacts with the compound represented by formula F to obtain the compound represented by formula H. The reaction formula is as follows: Preferably, the molar ratio of the compound represented by formula E to the compound represented by formula F is 1:2.2; Preferably, the reaction of the compound represented by formula E and the compound represented by formula F is carried out in the presence of a basic substance; Preferably, the alkaline substance is selected from N,N-diisopropylethylamine; Preferably, the reaction of the compound represented by formula E and the compound represented by formula F is carried out in the presence of an activating agent. Preferably, the activator is selected from 1-hydroxybenzotriazole and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride; Preferably, the reaction of the compound represented by Formula E with the compound represented by Formula F is carried out in a solvent, and the solvent is selected from dichloromethane and / or chloroform; Preferably, the reaction of the compound represented by Formula E and the compound represented by Formula F is carried out at room temperature for 12-24 hours.

9. A symmetrical phosphinic acid amino acid derivative, characterized in that: The symmetrical phosphinic acid amino acid derivative has a structure as shown in the following formula I: Wherein R is selected from hydrogen, substituted or unsubstituted C1-C10 alkyl, substituted or unsubstituted C6-C30 aryl, and R' is selected from amino acid side chains; Preferably, R' is selected from the side chain of any one of the 20 natural amino acids; Preferably, R' is selected from the group consisting of a glycine side chain, an alanine side chain, a valine side chain, a leucine side chain, a phenylalanine side chain or a proline side chain; Preferably, the symmetrical phosphinic acid amino acid derivative includes any one of the following compounds 9a-9g:

10. The method for preparing a symmetrical phosphinic acid amino acid derivative according to claim 9, characterized in that: The preparation method comprises the following steps: The compound represented by formula H is subjected to a deprotection reaction to obtain a compound represented by formula I. The reaction formula is as follows: Preferably, the deprotection reaction is carried out in the presence of an acid, and the acid is preferably trifluoroacetic acid; Preferably, the deprotection reaction is carried out in the presence of a carbocation capture agent; Preferably, the carbocation capture agent is selected from triisopropylsilane and water; Preferably, the deprotection reaction is carried out in a solvent, and the solvent is dichloromethane; Preferably, the deprotection reaction is to treat the compound represented by formula H with a mixture of dichloromethane, trifluoroacetic acid, triisopropylsilane and water, and react at room temperature for 12-24 hours to obtain the compound represented by formula I; Preferably, the volume ratio of dichloromethane, trifluoroacetic acid, triisopropylsilane and water is 50:50:0.1:0.

1.

11. Use of the symmetrical phosphinic acid amino acid derivative according to claim 10 in the preparation of HIV-1 protease inhibitors.

12. Use of the symmetrical phosphinic acid amino acid derivative according to claim 10 in the preparation of an inhibitor of T cell proliferation and activation.

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