CN109897088B

CN109897088B - Phenylalanine derivative containing N- (2-oxoethyl) benzene sulfonamide and preparation method and application thereof

Info

Publication number: CN109897088B
Application number: CN201910207029.XA
Authority: CN
Inventors: 刘新泳; 孙林; 展鹏; 黄天广; 巩志伟; 李国雄; 屈直言
Original assignee: Shandong University
Current assignee: Shandong University
Priority date: 2019-03-19
Filing date: 2019-03-19
Publication date: 2022-06-17
Anticipated expiration: 2039-03-19
Also published as: CN109897088A

Abstract

The invention provides a phenylalanine derivative containing N- (2-oxoethyl) benzene sulfonamide and a preparation method and application thereof. The derivative has a structure shown in the following general formula I. The invention also relates to a preparation method of the derivatives and application of the derivatives as HIV-1 inhibitors in preparing anti-AIDS drugs.

Description

Phenylalanine derivative containing N- (2-oxoethyl) benzene sulfonamide and preparation method and application thereof

Technical Field

The invention belongs to the technical field of organic compound synthesis and medical application, and particularly relates to a phenylalanine derivative containing N- (2-oxoethyl) benzenesulfonamide and a preparation method and application thereof.

Background

Acquired Immune Deficiency Syndrome (AIDS) is a serious infectious disease that endangers Human life and health, mainly caused by Human Immunodeficiency Virus Type I (HIV-1). Currently, clinically applied drugs for treating aids mainly include: reverse transcriptase inhibitors, protease inhibitors, integrase inhibitors and invasion inhibitors. The high-efficiency Antiretroviral Therapy (HAART) prolongs the survival time of patients to a great extent and improves the life quality of the patients, but the problems of drug resistance, drug toxic and side effects, latent infection, high cost of long-term taking of drugs and the like greatly reduce the efficacy of the Therapy, limit the application of the Therapy and further force researchers to develop anti-AIDS drugs with new targets, new mechanisms and new structures.

The HIV-1 capsid is assembled from a portion of the Gag precursor protein that is cleaved to yield capsid protein units. During the conversion of immature virions to mature virions, capsid proteins assemble into capsids, encapsulating viral RNA and nuclear-associated proteins (reverse transcriptase, protease, integrase, etc.) to form mature HIV-1 virions. The mature virion is infectious and the next round of replication of the virus can take place. In recent years, with the researchers' deep knowledge of capsid protein structure, the related information of crystal structure is reported in succession. Therefore, the capsid protein of HIV-1 can be used as the action target of a novel anti-HIV-1 medicament.

Pfizer company obtains a compound PF-74 capable of obviously inhibiting HIV-1 replication through high-throughput screening of a compound library, and the structure-activity relationship and mechanism research of the compound shows that the compound interferes with the process of virus uncoating and infectious particle formation by combining HIV-1 capsid protein. Although PF-74 has novel structure, unique mechanism and definite target, PF-74 has lower curative effect, poorer drug-like property and is easy to induce drug resistance compared with the anti-HIV-1 drugs on the market at present. Therefore, the development of capsid protein inhibitors with higher efficacy and good drug-like and drug-resistance has become an attractive direction in the development field of anti-aids drugs in recent years.

According to the crystal structure characteristics of the binding site of the PF-74 and the HIV-1 capsid protein, the invention discovers the phenylalanine HIV-1 capsid protein inhibitor of N- (2-oxoethyl) benzene sulfonamide with a brand-new structure through reasonable drug design, chemical synthesis and biological activity evaluation, and is expected to relieve the problems of poor drug property and drug resistance of the existing HIV-1 capsid protein inhibitor.

Disclosure of Invention

Aiming at the defects of the prior art, the invention provides a phenylalanine derivative containing N- (2-oxoethyl) benzene sulfonamide and a preparation method thereof, and also provides an activity screening result of the compound as an HIV-1 capsid protein inhibitor and application thereof.

The technical scheme of the invention is as follows:

1. phenylalanine derivatives containing N- (2-oxoethyl) benzenesulfonamide

A phenylalanine derivative containing N- (2-oxoethyl) benzenesulfonamide, or a pharmaceutically acceptable salt, ester or prodrug thereof, having a structure represented by general formula I:

wherein the content of the first and second substances,

r is as follows: c₁-C₆Alkyl, OC₁-C₆Alkyl radical, C₂-C₆Alkenyl radical, C₃-C₆Cycloalkyl, OC₃-C₆Cycloalkyl, substituted benzene ring, substituted benzyl, substituted naphthalene ring, various substituted six-membered heterocyclic rings or various substituted five-membered heterocyclic rings, H, OH, halogen, nitro, amino, cyano, trifluoromethyl or trifluoromethoxy.

According to a preferred embodiment of the present invention,

r is: H. 4-F, 3-F, 2-F, 4-Cl, 3-Cl, 2-Cl, 4-Br, 3-Br, 2-Br, 4-methoxy, 3-methoxy, 2-methoxy, 4-methyl, 3-methyl, 2-methyl, 3, 5-dimethyl, 2,4, 6-trimethyl, 4-nitro, 3-nitro, 2-nitro, 4-amino, 3-amino, 2-amino or 2,4, 6-triisopropyl.

According to a further preferred embodiment of the invention, the phenylalanine derivative containing N- (2-oxoethyl) benzenesulfonamide is one of the following compounds:

as used herein, "pharmaceutically acceptable salts" means salts of the compounds which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of human beings and lower animals without undue toxicity, irritation, and allergic response and the like, are commensurate with a reasonable benefit-to-risk ratio, are generally water or oil soluble or dispersible, and are effective for their intended use. Including pharmaceutically acceptable acid addition salts and pharmaceutically acceptable base addition salts, which are contemplated herein and are compatible with the chemical nature of the compounds of formula I. A list of suitable salts is found on pages 1-19 of s.m. berge et al, j.pharm.sci.,1977, 66.

The term "prodrug" as used herein refers to pharmaceutically acceptable derivatives such that the resulting biotransformation product of these derivatives is the active drug as defined for the compound of formula I.

2. Process for preparing phenylalanine derivatives containing N- (2-oxoethyl) benzenesulfonamide

A method for preparing phenylalanine derivatives containing N- (2-oxoethyl) benzenesulfonamide, comprising the steps of: generating an intermediate 2 with Boc-L-phenylalanine 1 as an initial raw material and dichloromethane as a reaction solvent through an amide condensation reaction and N-methyl-4-aminoanisole; then the intermediate 2 is dissolved in a proper amount of dichloromethane, and Boc groups are removed under the action of trifluoroacetic acid to obtain an intermediate 3; then, carrying out amide condensation reaction on the intermediate 3 and N-Boc-glycine to obtain an intermediate 4; then dissolving the intermediate 4 in a proper amount of dichloromethane solution, and removing Boc group under the action of trifluoroacetic acid to obtain an intermediate 5; finally, the intermediate 5 and the corresponding substituted benzene sulfonyl chloride are subjected to sulfonylation reaction to obtain a target compound (6 a-n); the compound (6e, m, n) is further reduced by hydrogenation to obtain the target compound (6 o-q).

The synthetic route is as follows:

reagents and conditions: (i) n-methyl-4-aminoanisole, 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate, N, N-diisopropylethylamine and dichloromethane are added, and the temperature is changed to room temperature at 0 ℃; (ii) trifluoroacetic acid, dichloromethane, room temperature; (iii) N-Boc-glycine, O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, N, N-diisopropylethylamine and dichloromethane are stirred at 0 ℃ to room temperature; (iv) trifluoroacetic acid, dichloromethane, room temperature; (v) correspondingly substituted benzene sulfonyl chloride, triethylamine and dichloromethane are cooled to room temperature at 0 ℃; (vi) h₂10% Pd. C, dichloromethane/methanol, room temperature.

Wherein R is as described in formula I above.

The substituted benzene sulfonyl chloride is benzene sulfonyl chloride, 4-fluorobenzene sulfonyl chloride, 3-fluorobenzene sulfonyl chloride, 2-fluorobenzene sulfonyl chloride, 4-chlorobenzene sulfonyl chloride, 4-bromobenzene sulfonyl chloride, 4-methoxybenzene sulfonyl chloride, 4-methylbenzene sulfonyl chloride, 4-nitrobenzene sulfonyl chloride, 3-nitrobenzene sulfonyl chloride, 2-nitrobenzene sulfonyl chloride, 3, 5-dimethylbenzene sulfonyl chloride, 2,4, 6-trimethylbenzene sulfonyl chloride and 2,4, 6-triisopropylbenzene sulfonyl chloride.

The room temperature of the invention is 20-30 ℃.

The preferable preparation method of the phenylalanine derivative containing the N- (2-oxoethyl) benzene sulfonamide comprises the following steps:

(1) adding Boc-L-phenylalanine 1 and 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate into dichloromethane, and stirring for 30min under an ice bath condition; adding N, N-diisopropylethylamine and N-methyl-4-aminoanisole into the reaction solution, removing the ice bath, transferring to room temperature, and monitoring by TLC; after the reaction is finished, evaporating the solvent under reduced pressure, then adding a saturated sodium bicarbonate solution into the residue in the bottle, extracting with dichloromethane, separating an organic phase, adding a 1N HCl solution for washing, separating the organic phase, adding a saturated sodium chloride solution for washing, drying the organic phase with anhydrous sodium sulfate, filtering, concentrating the filtrate under reduced pressure, and separating and purifying the obtained crude product by silica gel column chromatography to obtain an intermediate 2;

(2) adding the intermediate 2 obtained in the previous step into dichloromethane, slowly dropwise adding excessive trifluoroacetic acid into the solution under the condition of ice bath and stirring, then removing the ice bath, transferring to room temperature, and monitoring by TLC; after the reaction is finished, the solvent is removed by reduced pressure distillation, then saturated sodium bicarbonate solution is added to adjust the pH value of the reaction solution to 7, and dichloromethane solution is added to extract; separating and taking an organic phase, washing the organic phase for 3 times by using a saturated sodium chloride solution, drying the organic phase by using anhydrous sodium sulfate, filtering, and evaporating the solvent to dryness under reduced pressure to obtain an intermediate 3;

(3) adding N-Boc-glycine and O- (7-azabenzotriazole-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate into dichloromethane, and stirring for 1h under an ice bath condition; then adding the intermediate 3 and N, N-diisopropylethylamine into the solution, removing the ice bath, and stirring at room temperature for 6 h; after the reaction is finished, filtering, decompressing and evaporating the solvent, and separating by silica gel column chromatography to obtain an intermediate 4;

(4) adding the intermediate 4 into dichloromethane, slowly adding trifluoroacetic acid into the dichloromethane under the condition of ice bath and stirring, then removing the ice bath, transferring the mixture to room temperature, and monitoring by TLC; after the reaction is finished, the solvent is removed by reduced pressure distillation, then saturated sodium bicarbonate solution is added to adjust the pH value of the reaction solution to 7, and dichloromethane solution is added to extract; separating organic phase, washing with saturated sodium chloride solution for 3 times, drying organic phase with anhydrous sodium sulfate, filtering, and evaporating solvent under reduced pressure to obtain intermediate 5;

(5) adding the intermediate 5 and triethylamine into dichloromethane, slowly adding the corresponding substituted benzenesulfonyl chloride into the dichloromethane under the condition of ice bath and stirring, then removing the ice bath, transferring to room temperature, and monitoring by TLC; after the reaction is finished, adding a saturated sodium chloride solution, extracting by dichloromethane, separating an organic phase, drying by using anhydrous sodium sulfate, filtering, decompressing and evaporating the solvent, separating by silica gel column chromatography to obtain a crude product of the target compound, and recrystallizing by using ethyl acetate to obtain a pure product (6a-n) of the target compound;

(6) dissolving a target compound (6e, m, n) in methanol and dichloromethane, adding 10% Pd & C, replacing with hydrogen for three times, and stirring at room temperature for two hours under the protection of a hydrogen balloon; after the reaction is finished, adding diatomite for filtration, evaporating the filtrate to dryness to obtain a crude product of the target compound, and purifying by a silica gel preparation plate to obtain a pure product (6o-q) of the target compound.

3. Use of phenylalanine derivatives containing N- (2-oxoethyl) benzenesulfonamide

The invention discloses a screening result of anti-HIV-1 activity of phenylalanine derivatives containing N- (2-oxoethyl) benzene sulfonamide and application of the phenylalanine derivatives as HIV-1 inhibitors for the first time. Experiments prove that the phenylalanine derivative containing the N- (2-oxoethyl) benzene sulfonamide can be used as an HIV-1 inhibitor for preparing anti-AIDS medicaments. The invention also provides application of the compound in preparing anti-HIV-1 medicines.

anti-HIV-1 Activity and toxicity test of the target Compound

A class of phenylalanine derivatives containing N- (2-oxoethyl) benzenesulfonamide synthesized as described above was tested for anti-HIV-1 activity and toxicity at the cellular level, and their anti-HIV-1 activity and toxicity data are shown in Table 1, with the capsid protein inhibitor PF-74 reported in the literature as a positive control.

The newly synthesized N- (2-oxoethyl) benzene sulfonamide-containing phenylalanine derivative has remarkable anti-HIV-1 activity. For example, EC of the target compounds 6a, 6b, 6g, 6k, 6o₅₀In the range of 5.61-6.81. mu.M, wherein the anti-HIV-1 activity (EC) of the target compound 6k₅₀＝5.61±1.54μM,CC₅₀>40.0) is particularly prominent, and has value for further research.

The phenylalanine derivatives containing N- (2-oxoethyl) benzene sulfonamide can be used as HIV-1 inhibitors. In particular to the application of the compound as an HIV-1 inhibitor in preparing anti-AIDS drugs.

An anti-HIV-1 pharmaceutical composition comprises the phenylalanine derivatives containing N- (2-oxoethyl) benzene sulfonamide and one or more pharmaceutically acceptable carriers or excipients.

The invention provides a phenylalanine derivative containing N- (2-oxoethyl) benzene sulfonamide and a preparation method thereof, and also provides a screening result of anti-HIV-1 activity of partial compounds and the first application thereof in the field of antivirus. Tests prove that the phenylalanine derivatives containing N- (2-oxoethyl) benzene sulfonamide can be used as HIV-1 inhibitors and have high application value. In particular to the application of the compound as an HIV-1 inhibitor in preparing anti-AIDS drugs.

Detailed Description

The invention will be understood by the following examples, which are given by way of illustration and are not intended to limit the scope of the invention.

Example 1: preparation of tert-butyl (S) - (1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) carbamate (2)

The starting material Boc-L-phenylalanine (1) (2.90g,10.93mmol,1.5eq.) and 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate (5.69g,10.93mmol,1.5eq.) were added to 20mL of dichloromethane and stirred for 30min under ice-bath conditions; then N, N-diisopropylethylamine (3.61mL,21.87mmol,3eq.) and N-methyl-4-aminoanisole (1.0g, 7.29mmol,1eq.) were added, the ice bath was removed and the mixture was stirred at room temperature and monitored by TLC; after the reaction is finished after 6h, the solvent is evaporated under reduced pressure, then 40mL of saturated sodium bicarbonate solution and 40mL of dichloromethane are added into the residue in the bottle for extraction, the organic phase is separated and washed by 40mL of 1N HCl solution, the organic phase is separated and washed by 40mL of saturated sodium chloride solution, the organic phase is dried by anhydrous sodium sulfate, the filtration is carried out, the filtrate is concentrated under reduced pressure, and the obtained crude product is subjected to silica gel column chromatography (eluent EA: PE ═ 1:8) to obtain 2.48g of crude product of the intermediate (S) - (1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) carbamic acid tert-butyl ester (2) and yellow oily matter with the yield of 89%.

Spectral data:

¹H NMR(400MHz,DMSO-d₆)δ7.22(d,J＝8.3Hz,2H,Ph-H),7.20–7.11(m,3H,Ph-H),7.09(d,J＝8.2Hz,1H,NH),7.03(d,J＝8.6Hz,2H,Ph-H),6.79(d,J＝7.3Hz,2H,Ph-H),4.27–4.06(m,1H,CH),3.81(s,3H,OCH₃),3.13(s,3H,NCH₃),2.75(dd,J＝13.4,3.8Hz,1H,PhCH),2.61(dd,J＝13.3,10.3Hz,1H,PhCH),1.30(s,9H,C(CH₃)₃).

¹³C NMR(100MHz,DMSO-d₆)δ172.22(C＝O),158.98,155.75(C＝O),138.53(2×C),136.12(2×C),129.28(2×C),128.47(2×C),126.70,115.21(2×C),78.33,55.94,53.55,37.86,37.07,28.65(3×C).

ESI-MS:m/z 385.4(M+1),407.5(M+23).C₂₂H₂₈N₂O₄[384.5].

example 2: preparation of (S) -2-amino-N- (4-methoxyphenyl) -N-methyl-3-phenylpropionamide (3)

Intermediate 2(4.0g,10.40mmol,1.0eq.) was added to 30mL dichloromethane, then trifluoroacetic acid (3.86mL,52.02mmol,5.0eq.) was added slowly to this solution, stirred at room temperature, monitored by TLC; after 1h, the reaction was completed, and then the reaction solution was adjusted to pH 7 with saturated sodium bicarbonate solution, extracted with 40mL of dichloromethane, the organic phase was separated, washed with saturated sodium chloride solution (20 mL. times.3 times), dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure to obtain 2.36g of a crude product of intermediate (S) -2-amino-N- (4-methoxyphenyl) -N-methyl-3-phenylacrylamide (3), as a yellow oil, in 80% yield.

Spectral data:

¹H NMR(400MHz,DMSO-d₆)δ7.29–7.13(m,3H,Ph-H),7.03–6.75(m,6H,Ph-H),3.77(s,3H,OCH₃),3.44–3.35(m,1H,CH),3.06(s,3H,NCH₃),2.75(dd,J＝12.8,6.7Hz,1H,PhCH),2.45(dd,J＝12.9,7.1Hz,1H,PhCH),1.87(s,2H,NH₂).

¹³C NMR(100MHz,DMSO-d₆)δ174.89(C＝O),158.75,139.00,136.35,129.51(2×C),128.93(2×C),128.47(2×C),126.55,115.04(2×C),55.85,53.35,42.19,37.45.

ESI-MS:m/z 285.05(M+1).C₁₇H₂₀N₂O₂[284.36].

example 3: preparation of intermediate (S) - (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) carbamic acid tert-butyl ester (4)

N-Boc-glycine (1.62g,9.24mmol,1.2eq.) and O- (7-azabenzotriazol-1-yl) -N, N' -tetramethyluronium hexafluorophosphate (4.39g,11.15mmol,1.5eq.) were added to 20mL of dichloromethane and stirred under ice-bath conditions for 1 h; to this solution was then added intermediate 3(2.19g,7.70mmol,1eq.) and N, N-diisopropylethylamine (2.55mL,15.40mmol,2eq.), stirred at room temperature after removal of the ice bath, monitored by TLC; after 6h the reaction was complete, the solvent was evaporated off under reduced pressure and the intermediate tert-butyl (S) - (2- ((1- ((4-methoxyphenyl) (methyl) amino) -1-oxo-3-phenylpropan-2-yl) amino) -2-oxoethyl) carbamate (4) was obtained by column chromatography on silica gel (eluent EA: PE ═ 1:4+ 2.5% triethylamine) 2.73g as a white solid in 80% yield: 79 to 80 ℃.

Spectral data:

¹H NMR(400MHz,DMSO-d₆)δ8.08(d,J＝7.8Hz,1H,NH),7.26–7.15(m,3H,Ph-H),7.14–7.01(m,2H,BocNH+Ph-H),6.96(d,J＝8.8Hz,2H,Ph-H),6.93–6.79(m,3H,Ph-H),4.44(q,J＝8.0Hz,1H,CH),3.79(s,3H,OCH₃),3.53(dd,J＝16.9,6.1Hz,1H,BocNCH),3.45(dd,J＝16.8,6.0Hz,1H,BocNCH),3.09(s,3H,NCH₃),2.84(dd,J＝13.3,5.2Hz,1H,PhCH),2.63(dd,J＝13.3,8.7Hz,1H,PhCH),1.37(s,9H,C(CH₃)₃).

¹³C NMR(100MHz,DMSO-d₆)δ171.46(C＝O),169.31(C＝O),158.97,156.11(C＝O),137.84,135.91,129.36(2×C),129.10(2×C),128.60(2×C),126.89,115.07(2×C),78.42,55.87,51.63,43.19,37.99,37.76,28.66(3×C).

ESI-MS:m/z 442.5(M+1),464.5(M+23).C₂₄H₃₁N₃O₅[441.5].

example 4: preparation of intermediate (S) -2- (2-aminoacetamido) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5)

Intermediate 4(2.7g,6.11mmol) was added to dichloromethane (20mL) and trifluoroacetic acid (5mL) was added slowly thereto with stirring in an ice bath, followed by removal of the ice bath to room temperature and monitoring by TLC; after the reaction is finished after 12h, the solvent is evaporated under reduced pressure, then saturated sodium bicarbonate solution is added to adjust the pH of the reaction solution to 7, and then 30mL of dichloromethane solution is added for extraction; the organic phase was separated, washed with saturated sodium chloride solution (30mL × 3 times), dried over anhydrous sodium sulfate, filtered, and the solvent was evaporated under reduced pressure to give 1.53g of intermediate (S) -2- (2-aminoacetamido) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropanamide (5) as a yellow oil in 73% yield.

Spectral data:

ESI-MS:m/z 342.3(M+1),364.4(M+23).C₁₉H₂₃N₃O₃[341.4].

example 5: preparation of target Compound (6a-n)

Dissolving the intermediate 5(1eq.) and triethylamine (2eq.) in 10mL of dichloromethane, slowly adding the corresponding substituted benzenesulfonyl chloride (1.2 or 1.5eq.) while stirring in an ice bath, removing the ice bath, transferring to room temperature, and monitoring by TLC; after the reaction is finished, 30mL of saturated sodium chloride solution is added, then dichloromethane is added for extraction (20mL multiplied by 3 times), an organic phase is separated, anhydrous sodium sulfate is used for drying, filtration is carried out, the solvent is evaporated to dryness under reduced pressure, a crude product of the target compound is obtained, and the crude product of the target compound is purified by a silica gel preparation plate or recrystallized by ethyl acetate to obtain a pure product (6a-n) of the target compound.

The correspondingly substituted benzenesulfonyl chloride was reacted with benzenesulfonyl chloride (112 μ L,0.88mmol,1.5eq.) with intermediate 5(200mg,0.59mmol, 1eq.) and triethylamine (162 μ L,1.17mmol,2eq.) to give 130mg of (S) -N- (4-methoxyphenyl) -N-methyl-3-phenyl-2- (2- (phenylsulfonylamino) acetylamino) propionamide (6a) as a white powdery solid in 47% yield, m.p.: 69-70 ℃.

Spectral data:

¹H NMR(400MHz,DMSO-d₆)δ8.20(d,J＝7.9Hz,1H,NH),7.87(t,J＝6.1Hz,1H,SO₂NH),7.76(d,J＝7.3Hz,2H,Ph-H),7.63(t,J＝7.3Hz,1H,Ph-H),7.56(t,J＝7.4Hz,2H,Ph-H),7.24–7.14(m,3H,Ph-H),7.02–6.89(m,4H,Ph-H),6.89–6.81(m,2H,Ph-H),4.36(td,J＝8.1,5.9Hz,1H,CH),3.79(s,3H,OCH₃),3.49–3.36(m,2H,SO₂NCH₂),3.08(s,3H,NCH₃),2.81(dd,J＝13.4,5.7Hz,1H,PhCH),2.56(dd,J＝13.4,8.5Hz,1H,PhCH).

¹³C NMR(100MHz,DMSO-d₆)δ171.15(C＝O),167.24(C＝O),158.95,140.74,137.62,135.80,132.84,129.51(2×C),129.36(2×C),129.05(2×C),128.62(2×C),127.01(2×C),126.95,115.03(2×C),55.87,51.52,45.22,38.05,37.75.

ESI-HRMS:m/z 482.1748(M+1),985.3245(2M+23).C₂₅H₂₇N₃O₅S[481.1671].

reaction of the correspondingly substituted benzenesulfonyl chloride with 4-fluorobenzenesulfonyl chloride (150mg,0.75mmol,1.5eq.) with intermediate 5(170g,0.50mmol, 1eq.), triethylamine (137 μ L,1.00mmol,2eq.) gave 113mg of (S) -2- (2- ((4-fluorophenyl) sulfonamido) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropionamide (6b) as a white solid in 46% yield, m.p.: 75-76 ℃.

Spectral data:

¹H NMR(400MHz,DMSO-d₆)δ8.24(d,J＝7.9Hz,1H,NH),7.92(t,J＝5.4Hz,1H,SO₂NH),7.80(dd,J＝8.7,5.3Hz,2H,Ph-H),7.36(t,J＝8.8Hz,2H,Ph-H),7.25–7.15(m,3H,Ph-H),7.01–6.88(m,4H,Ph-H),6.88–6.80(m,2H,Ph-H),4.32(td,J＝8.1,6.0Hz,1H,CH),3.79(s,3H,OCH₃),3.49(dd,J＝16.4,4.7Hz,1H,SO₂NCH),3.39(dd,J＝16.9,4.8Hz,1H,SO₂NCH),3.08(s,3H,NCH₃),2.81(dd,J＝13.4,5.6Hz,1H,PhCH),2.55(dd,J＝13.4,8.7Hz,1H,PhCH).

¹³C NMR(100MHz,DMSO-d₆)δ171.14(C＝O),167.18(C＝O),164.53(d,¹J_CF＝248.8Hz),158.96,137.64,137.22(d,⁴J_CF＝3.0Hz),135.80,130.13,130.03,129.35(2×C),129.01(2×C),128.62(2×C),126.95,116.64,116.41,115.00(2×C),55.85,51.56,45.15,38.02,37.71.

ESI-HRMS:m/z 500.1651(M+1),1021.3082(2M+23).C₂₅H₂₆FN₃O₅S[499.1577].

the corresponding substituted benzenesulfonyl chloride was reacted with 4-chlorobenzenesulfonyl chloride (167mg,0.79mmol,1.5eq.) with intermediate 5(180mg,0.53mmol, 1eq.), triethylamine (151 μ L,1.05mmol,2eq.) to give (S) -2- (2- ((4-chlorophenyl) sulfonamido) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropionamide (6c)87mg as white needles in 32% yield, melting point: 152 ℃ and 153 ℃.

Spectral data:

¹H NMR(400MHz,DMSO-d₆)δ8.25(d,J＝7.9Hz,1H,NH),8.00(s,1H,SO₂NH),7.73(d,J＝8.5Hz,2H,Ph-H),7.59(d,J＝8.6Hz,2H,Ph-H),7.26–7.15(m,3H,Ph-H),7.06–6.89(m,4H,Ph-H),6.84(dd,J＝6.9,2.0Hz,2H,Ph-H),4.31(td,J＝8.1,5.9Hz,1H,CH),3.79(s,3H,OCH₃),3.51(d,J＝16.7Hz,1H,SO₂NCH),3.40(d,J＝16.8Hz,1H,SO₂NCH),3.08(s,3H,NCH₃),2.80(dd,J＝13.4,5.7Hz,1H,PhCH),2.61–2.52(m,1H,PhCH).

¹³C NMR(100MHz,DMSO-d₆)δ171.15(C＝O),167.13(C＝O),158.96,139.77,137.64,137.62,135.79,129.51(2×C),129.35(2×C),129.03(2×C),129.01(2×C),128.62(2×C),126.95,115.00(2×C),55.86,51.54,45.12,38.03,37.73.

ESI-HRMS:m/z 516.1351(M+1),1053.2422(2M+23).C₂₅H₂₆ClN₃O₅S[515.1282].

reaction of the corresponding substituted benzenesulfonyl chloride with 4-bromobenzenesulfonyl chloride (192mg,0.70mmol,1.5eq.) with intermediate 5(160mg,0.47mmol, 1eq.), triethylamine (139 μ L,0.94mmol,2eq.) gave 92mg of (S) -2- (2- ((4-bromophenyl) sulfonamido) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropionamide (6d) as a white solid in 35% yield, melting point: 167 ℃ and 168 ℃.

Spectral data:

¹H NMR(400MHz,DMSO-d₆)δ8.25(d,J＝7.9Hz,1H,NH),8.00(s,1H,SO₂NH),7.74(d,J＝8.5Hz,2H,Ph-H),7.66(d,J＝8.5Hz,2H,Ph-H),7.26–7.14(m,3H,Ph-H),7.01–6.89(m,4H,Ph-H),6.87–6.79(m,2H,Ph-H),4.32(td,J＝8.1,6.2Hz,1H,CH),3.79(s,3H,OCH₃),3.58–3.46(m,1H,SO₂NCH),3.40(dd,J＝17.0,3.6Hz,1H,SO₂NCH),3.09(s,3H,NCH₃),2.80(dd,J＝13.4,5.7Hz,1H,PhCH),2.60–2.52(m,1H,PhCH).

¹³C NMR(100MHz,DMSO-d₆)δ171.16(C＝O),167.12(C＝O),158.96,140.20,137.64,135.78,132.45(2×C),129.35(2×C),129.13(2×C),129.01(2×C),128.62(2×C),126.95,126.58,115.00(2×C),55.87,51.53,45.12,38.05,37.74.

ESI-HRMS:m/z 560.0851(M+1).C₂₅H₂₆BrN₃O₅S[559.0777].

the corresponding substituted benzenesulfonyl chloride was reacted with 4-nitrobenzenesulfonyl chloride (132mg,0.60mmol,1.2eq.) with intermediate 5(170mg,0.50mmol, 1eq.), triethylamine (138 μ L,1.00mmol,2eq.) to give 103mg of (S) -N- (4-methoxyphenyl) -N-methyl-2- (2- ((4-nitrophenyl) sulfonamido) acetamido) -3-phenylpropanamide (6e) as a white solid in 39% yield, melting point: 226 ℃ 227 ℃.

Spectral data:

¹H NMR(400MHz,DMSO-d₆)δ8.33(d,J＝8.7Hz,4H,NH+SO₂NH+Ph-H×2),7.95(d,J＝8.8Hz,2H,Ph-H),7.32–7.13(m,3H,Ph-H),7.01–6.86(m,4H,Ph-H),6.86–6.75(m,2H,Ph-H),4.34–4.19(m,1H,CH),3.78(s,3H,OCH₃),3.61(d,J＝16.4Hz,1H,SO₂NCH),3.49(d,J＝16.6Hz,1H,SO₂NCH),3.06(s,3H,NCH₃),2.80(dd,J＝13.4,5.5Hz,1H,PhCH),2.62–2.53(m,1H,PhCH).

¹³C NMR(100MHz,DMSO-d₆)δ171.17(C＝O),167.07(C＝O),158.96,149.81,146.66,137.67,135.76,129.32(2×C),128.97(2×C),128.66(2×C),128.62(2×C),126.95,124.65(2×C),114.92(2×C),55.83,51.67,45.06,37.91,37.67.

ESI-HRMS:m/z 527.1596(M+1),1075.2943(2M+23).C₂₅H₂₆N₄O₇S[526.1522].

the corresponding substituted benzenesulfonyl chloride was reacted with 4-methoxybenzenesulfonyl chloride (109mg,0.53mmol,1.2eq.) with intermediate 5(150mg,0.44mmol, 1eq.), triethylamine (122 μ L,0.88mmol,2eq.) to give (S) -N- (4-methoxyphenyl) -2- (2- ((4-methoxyphenyl) sulfonamido) acetamido) -N-methyl-3-phenylpropanamide (6f)142mg as a white solid in 63% yield, melting point: 76-77 ℃.

Spectral data:

¹H NMR(400MHz,DMSO-d₆)δ8.17(d,J＝7.9Hz,1H,NH),7.76–7.63(m,3H,SO₂NH+Ph-H×2),7.27–7.16(m,3H,Ph-H),7.05(d,J＝8.8Hz,2H,Ph-H),7.01–6.89(m,4H,Ph-H),6.89–6.81(m,2H,Ph-H),4.35(td,J＝8.0,5.9Hz,1H,CH),3.80(s,3H,OCH₃),3.79(s,3H,OCH₃),3.46–3.35(m,2H,SO₂NCH₂),3.08(s,3H,NCH₃),2.81(dd,J＝13.4,5.7Hz,1H,PhCH),2.55(dd,J＝13.6,8.7Hz,1H,PhCH).

¹³C NMR(100MHz,DMSO-d₆)δ171.15(C＝O),167.31(C＝O),162.59,158.95,137.62,135.81,132.34,129.36(2×C),129.25(2×C),129.02(2×C),128.62(2×C),126.95,115.01(2×C),114.61(2×C),56.06,55.86,51.52,45.26,38.09,37.73.

ESI-HRMS:m/z 512.1850(M+1),1045.3434(2M+23).C₂₆H₂₉N₃O₆S[511.1777].

the corresponding substituted benzenesulfonyl chloride was reacted with 4-methylbenzenesulfonyl chloride (92mg,0.49mmol,1.2eq.) with intermediate 5(140mg,0.41mmol, 1eq.), triethylamine (111 μ L,0.82mmol,2eq.) to give 157mg of (S) -N- (4-methoxyphenyl) -N-methyl-2- (2- ((4-methylphenyl) sulfonamido) acetamido) -3-phenylpropanamide (6g) as a white solid in 78% yield, melting point: and (6) from 66 to 67 ℃.

Spectral data:

¹H NMR(400MHz,DMSO-d₆)δ8.23(d,J＝7.9Hz,1H,NH),7.81(t,J＝6.0Hz,1H,SO₂NH),7.69(d,J＝8.1Hz,2H,Ph-H),7.39(d,J＝8.1Hz,2H,Ph-H),7.33–7.20(m,3H,Ph-H),7.10–6.94(m,4H,Ph-H),6.94–6.85(m,2H,Ph-H),4.40(td,J＝8.0,6.1Hz,1H,CH),3.84(s,3H,OCH₃),3.51–3.41(m,2H,SO₂NCH₂),3.13(s,3H,NCH₃),2.86(dd,J＝13.4,5.7Hz,1H,PhCH),2.65–2.57(m,1H,PhCH),2.41(s,3H,PhCH₃).

¹³C NMR(100MHz,DMSO-d₆)δ171.16(C＝O),167.26(C＝O),158.95,143.05,137.84,137.62,135.81,129.92(2×C),129.35(2×C),129.02(2×C),128.62(2×C),127.10(2×C),126.95,115.02(2×C),55.87,51.52,45.24,38.08,37.74,21.42.

ESI-HRMS:m/z 496.1898(M+1),1013.3557(2M+23).C₂₆H₂₉N₃O₅S[495.1828].

reaction of the correspondingly substituted benzenesulfonyl chloride with 3, 5-dimethylbenzenesulfonyl chloride (115mg,0.56mmol,1.2eq.) with intermediate 5(160mg,0.47mmol, 1eq.), triethylamine (130 μ L,0.94mmol,2eq.) gave (S) -2- (2- ((3, 5-dimethylphenyl) sulfonamido) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropionamide (6h)137mg as a white solid in 57% yield, melting point: 156 ℃ and 157 ℃.

Spectral data:

¹H NMR(400MHz,DMSO-d₆)δ8.19(d,J＝7.9Hz,1H,NH),7.79(t,J＝6.1Hz,1H,SO₂NH),7.49–7.41(m,2H,Ph-H),7.32(s,1H,Ph-H),7.29–7.19(m,3H,Ph-H),7.07–6.94(m,4H,Ph-H),6.94–6.84(m,2H,Ph-H),4.44(q,J＝8.0Hz,1H,CH),3.84(s,3H,OCH₃),3.53–3.40(m,2H,SO₂NCH₂),3.13(s,3H,NCH₃),2.86(dd,J＝13.4,5.8Hz,1H,PhCH),2.68–2.58(m,1H,PhCH),2.39(s,6H,PhCH₃×2).

¹³C NMR(100MHz,DMSO-d₆)δ171.13(C＝O),167.32(C＝O),158.96,140.52,139.02(2×C),137.58,135.80,134.18,129.35(2×C),129.03(2×C),128.63(2×C),126.96,124.53(2×C),115.02(2×C),55.87,51.50,45.26,38.10,37.73,21.23(2×C).

ESI-HRMS:m/z 510.2059(M+1),1041.3879(2M+23).C₂₇H₃₁N₃O₅S[509.1984].

the corresponding substituted benzenesulfonyl chloride was selected from 2,4, 6-trimethylbenzenesulfonyl chloride (113mg,0.52mmol,1.2eq.) and reacted with intermediate 5(147mg,0.43mmol, 1eq.), triethylamine (119 μ L,0.86mmol,2eq.) to give 76mg of (S) -N- (4-methoxyphenyl) -N-methyl-3-phenyl-2- (2- ((2,4, 6-trimethylphenyl) sulfonamido) acetamide (6i) as a white solid in 34% yield and melting point: 64-65 ℃.

Spectral data:

¹H NMR(400MHz,DMSO-d₆)δ8.14(d,J＝8.0Hz,1H,NH),7.63(t,J＝6.1Hz,1H,SO₂NH),7.31–7.20(m,3H,Ph-H),7.02(s,2H,Ph-H),6.98–6.83(m,6H,Ph-H),4.34(q,J＝7.7Hz,1H,CH),3.83(s,3H,OCH₃),3.48–3.42(m,2H,SO₂NCH₂),3.10(s,3H,NCH₃),2.81(dd,J＝13.3,6.2Hz,1H,PhCH),2.57(s,6H,PhCH₃×2),2.50(dd,J＝13.3,8.0Hz,1H,PhCH),2.25(s,3H,PhCH₃).

¹³C NMR(100MHz,DMSO-d₆)δ171.06(C＝O),167.34(C＝O),158.90,141.76,138.93(2×C),137.54,135.76,134.70,131.96(2×C),129.35(2×C),128.95(2×C),128.61(2×C),126.93,114.98(2×C),55.85,51.37,44.49,38.25,37.70,23.05(2×C),20.83.

ESI-HRMS:m/z 524.2215(M+1),1069.4181(2M+23).C₂₈H₃₃N₃O₅S[523.2141].

reaction of the corresponding substituted benzenesulfonyl chloride with 2-fluorobenzenesulfonyl chloride (101mg,0.52mmol,1.2eq.) with intermediate 5(148mg,0.43mmol, 1eq.), triethylamine (120 μ L,0.87mmol,2eq.) gave 137mg of (S) -2- (2- ((2-fluorophenyl) sulfonamido) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropionamide (6j) as a white solid in 63% yield, m.p.: 126 ℃ and 127 ℃.

Spectral data:

¹H NMR(400MHz,DMSO-d₆)δ8.26(d,J＝7.9Hz,1H,NH),8.14(s,1H,SO₂NH),7.84–7.67(m,2H,Ph-H),7.51–7.40(m,1H,Ph-H),7.37(t,J＝7.6Hz,1H,Ph-H),7.30–7.20(m,3H,Ph-H),6.97(s,4H,Ph-H),6.94–6.84(m,2H,Ph-H),4.39(q,J＝7.9Hz,1H,CH),3.84(s,3H,OCH₃),3.61(q,J＝16.9Hz,2H,SO₂NCH₂),3.12(s,3H,NCH₃),2.85(dd,J＝13.4,5.9Hz,1H,PhCH),2.67–2.58(m,1H,PhCH).

¹³C NMR(100MHz,DMSO-d₆)δ171.12(C＝O),167.32(C＝O),158.92,158.77(d,¹J_CF＝251.9Hz),137.61,135.80,135.45(d,³J_CF＝8.7Hz),129.81(2×C),129.36(2×C),129.02(2×C),128.62(2×C),126.94,125.02(d,⁴J_CF＝3.4Hz),117.50(d,²J_CF＝21.0Hz),115.01(2×C),55.87,51.51,45.03,38.10,37.73.

ESI-HRMS:m/z 500.1645(M+1),1021.3026(2M+23).C₂₅H₂₆FN₃O₅S[499.1577].

reaction of the corresponding substituted benzenesulfonyl chloride with 3-fluorobenzenesulfonyl chloride (70 μ L,0.53mmol,1.2eq.) with intermediate 5(150mg,0.44mmol, 1eq.), triethylamine (122 μ L,0.88mmol,2eq.) gave 125mg of (S) -2- (2- ((3-fluorophenyl) sulfonamido) acetylamino) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropionamide (6k) as a white solid in 57% yield, melting point: 114-.

Spectral data:

¹H NMR(400MHz,DMSO-d₆)δ8.30(d,J＝7.9Hz,1H,NH),8.09(s,1H,SO₂NH),7.72–7.59(m,3H,Ph-H),7.58–7.50(m,1H,Ph-H),7.30–7.18(m,3H,Ph-H),7.07–6.94(m,4H,Ph-H),6.94–6.85(m,2H,Ph-H),4.40(q,J＝8.0Hz,1H,CH),3.84(s,3H,OCH₃),3.56(d,J＝16.5Hz,1H,SO₂NCH),3.46(d,J＝16.6Hz,1H,SO₂NCH),3.13(s,3H,NCH₃),2.86(dd,J＝13.4,5.8Hz,1H,PhCH),2.61(dd,J＝13.2,8.2Hz,1H,PhCH).

¹³C NMR(100MHz,DMSO-d₆)δ171.12(C＝O),167.16(C＝O),162.11(d,¹J_CF＝246.3Hz),158.95,143.01(d,³J_CF＝6.7Hz),137.60,135.80,131.83(d,³J_CF＝7.9Hz),129.34(2×C),129.03,128.62(2×C),126.95,123.27,123.24,119.94(d,²J_CF＝21.1Hz),115.00(2×C),114.12(d,²J_CF＝24.2Hz),55.86,51.52,45.15,38.05,37.73.

ESI-HRMS:m/z 500.1650(M+1),1021.3056(2M+23).C₂₅H₂₆FN₃O₅S[499.1577].

the corresponding substituted benzenesulfonyl chloride was reacted with 2,4, 6-triisopropylbenzenesulfonyl chloride (170mg,0.56mmol,1.2eq.) and intermediate 5(160mg,0.47mmol, 1eq.) and triethylamine (130 μ L,0.94mmol,2eq.) to give 107mg of (S) -N- (4-methoxyphenyl) -N-methyl-3-phenyl-2- (2- ((2,4, 6-triisopropyl) sulfonamido) acetamido) (6L) as a white solid in 38% yield and melting point: 179 ℃ and 180 ℃.

Spectral data:

¹H NMR(400MHz,DMSO-d₆)δ8.13(d,J＝8.1Hz,1H,NH),7.53(t,J＝5.9Hz,1H,SO₂NH),7.23(s,2H,Ph-H),7.20–7.11(m,3H,Ph-H),6.97–6.80(m,6H,Ph-H),4.40(q,J＝7.8Hz,1H,CH),4.04(hept,J＝6.2Hz,2H,(CH₃)₂CH×2),3.78(s,3H,OCH₃),3.49–3.42(m,2H,SO₂NCH₂),3.05(s,3H,NCH₃),2.90(p,J＝6.8Hz,1H,(CH₃)₂CH),2.80(dd,J＝13.3,6.1Hz,1H,PhCH),2.55(d,J＝8.2Hz,1H,PhCH),1.23–1.17(m,18H,C(CH₃)₂×3).

¹³C NMR(100MHz,DMSO-d₆)δ171.09(C＝O),167.34(C＝O),158.91,152.41,150.05(2×C),137.52,135.74,133.67,129.37(2×C),129.00(2×C),128.58(2×C),126.93,123.95(2×C),114.99(2×C),55.84,51.45,46.06,38.27,37.71,33.78,29.44,25.23(2×C),25.20(2×C),23.92,23.86.

ESI-HRMS:m/z 608.3157(M+1),1237.6070(2M+23).C₃₄H₄₅N₃O₅S[607.3080].

the correspondingly substituted benzenesulfonyl chloride was reacted with 2-nitrobenzenesulfonyl chloride (147mg,0.66mmol,1.2eq.) with intermediate 5(189mg,0.55mmol,1eq), triethylamine (153 μ L,1.11mmol,2eq.) to give (S) -N- (4-methoxyphenyl) -N-methyl-2- (2- ((2-nitrophenyl) sulfonamido) acetamido) -3-phenylpropanamide (6m)169mg of a white solid in 58% yield, m.p.: 111 ℃ and 112 ℃.

Spectral data:

¹H NMR(400MHz,DMSO-d₆)δ8.30(d,J＝7.9Hz,1H,NH),8.15(s,1H,SO₂NH),8.03–7.92(m,2H,Ph-H),7.89–7.76(m,2H,Ph-H),7.24–7.14(m,3H,Ph-H),7.02–6.88(m,4H,Ph-H),6.88–6.79(m,2H,Ph-H),4.35(q,J＝8.1Hz,1H,CH),3.79(s,3H,OCH₃),3.66(d,J＝16.7Hz,1H,SO₂NCH),3.56(d,J＝16.8Hz,1H,SO₂NCH),3.07(s,3H,NCH₃),2.81(dd,J＝13.4,5.7Hz,1H,PhCH),2.60–2.53(m,1H,PhCH).

¹³C NMR(100MHz,DMSO-d₆)δ171.11(C＝O),167.16(C＝O),158.94,147.88,137.61,135.78,134.33,133.56,133.07,130.15,129.35(2×C),129.02,128.62(2×C),126.95,124.92(2×C),115.02(2×C),55.87,51.61,45.29,38.06,37.75.

ESI-HRMS:m/z 527.1593(M+1),1075.2935(2M+23).C₂₅H₂₆N₄O₇S[526.1522].

the corresponding substituted benzenesulfonyl chloride was reacted with 3-nitrobenzenesulfonyl chloride (117mg,0.53mmol,1.2eq.) with intermediate 5(150mg,0.44mmol, 1eq.), triethylamine (122 μ L,0.88mmol,2eq.) to give 105mg of (S) -N- (4-methoxyphenyl) -N-methyl-2- (2- ((3-nitrophenyl) sulfonamido) acetamido) -3-phenylpropanamide (6N) as a white solid in 46% yield, melting point: 80-81 ℃.

Spectral data:

¹H NMR(400MHz,DMSO-d₆)δ8.59–8.50(m,1H,Ph-H),8.50–8.43(m,1H,Ph-H),8.37–8.26(m,2H,Ph-H),8.13(d,J＝7.9Hz,1H,NH),7.83(t,J＝8.0Hz,1H,SO₂NH),7.25–7.12(m,3H,Ph-H),6.97–6.86(m,4H,Ph-H),6.86–6.74(m,2H,Ph-H),4.25(td,J＝8.1,5.9Hz,1H,CH),3.78(s,3H,OCH₃),3.60(d,J＝16.6Hz,1H,SO₂NCH),3.48(d,J＝16.8Hz,1H,SO₂NCH),3.04(s,3H,NCH₃),2.78(dd,J＝13.4,5.6Hz,1H,PhCH),2.58–2.52(m,1H,PhCH).

¹³C NMR(100MHz,DMSO-d₆)δ171.06(C＝O),167.07(C＝O),158.93,148.11,142.64,137.59,135.77,133.23,131.36,129.30(2×C),128.99(2×C),128.61(2×C),127.35,126.95,122.09,114.93(2×C),55.85,51.59,45.00,37.91,37.66.

ESI-HRMS:m/z 527.1591(M+1),1075.2938(2M+23).C₂₅H₂₆N₄O₇S[526.1522].

example 6: preparation of target Compound (6o-q)

Dissolve 6e (100mg,0.19mmol) in methanol: dichloromethane (5mL:5mL), then 10% Pd.C (10mg) is added, hydrogen is replaced for three times, and the mixture is stirred for two hours at room temperature under the protection of a hydrogen balloon; after the reaction is finished, adding diatomite for filtration, evaporating filtrate to dryness to obtain a crude product of the target compound, and purifying the crude product by using a silica gel preparation plate to obtain a pure product (S) -2- (2- ((4-aminophenyl) sulfonamido) acetamido) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropionamide (6o)40mg of the target compound, wherein the yield is 94% of a yellow solid, and the melting point is as follows: 90-91 ℃.

Spectral data:

¹H NMR(400MHz,DMSO-d₆)δ8.08(d,J＝8.0Hz,1H,NH),7.39(d,J＝8.6Hz,2H,Ph-H),7.29(t,J＝6.2Hz,1H,SO₂NH),7.24–7.14(m,3H,Ph-H),7.03–6.91(m,4H,Ph-H),6.90–6.79(m,2H,Ph-H),6.59(d,J＝8.7Hz,2H,Ph-H),5.96(s,2H,NH₂),4.41(td,J＝8.0,6.0Hz,1H,CH),3.78(s,3H,OCH₃),3.34–3.27(m,1H,SO₂NCH),3.22(dd,J＝16.4,6.3Hz,1H,SO₂NCH),3.09(s,3H,NCH₃),2.82(dd,J＝13.3,5.8Hz,1H,PhCH),2.57(dd,J＝13.4,8.3Hz,1H,PhCH).

¹³C NMR(100MHz,DMSO-d₆)δ171.11(C＝O),167.53(C＝O),158.95,153.09,137.59(2×C),135.79,129.39(2×C),129.06,128.62(2×C),126.94,125.27(2×C),115.05(2×C),113.02(2×C),55.86,51.40,45.38,38.18,37.75.

ESI-HRMS:m/z 497.1848(M+1),1015.3501(2M+23).C₂₅H₂₈N₄O₅S[496.1780].

dissolving 6m (100mg,0.19mmol) in methanol (5mL), adding 10% Pd.C (10mg), replacing with hydrogen for three times, and stirring at room temperature for two hours under the protection of hydrogen balloon; after the reaction is finished, adding diatomite for filtration, evaporating filtrate to dryness to obtain a crude product of the target compound, and purifying the crude product by using a silica gel preparation plate to obtain 46mg of a pure product (S) -2- (2- ((2-aminophenyl) sulfonamido) acetamido) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropionamide (6p) of the target compound, wherein the yield is 49 percent, and the melting point is as follows: 78-79 ℃.

Spectral data:

¹H NMR(400MHz,DMSO-d₆)δ8.17(d,J＝7.9Hz,1H,NH),7.68(t,J＝6.0Hz,1H,SO₂NH),7.51–7.42(m,1H,Ph-H),7.30–7.23(m,1H,Ph-H),7.23–7.14(m,3H,Ph-H),7.05–6.89(m,4H,Ph-H),6.89–6.83(m,2H,Ph-H),6.80(d,J＝8.1Hz,1H,Ph-H),6.59(t,J＝7.3Hz,1H,Ph-H),5.95(s,2H,NH₂),4.39(td,J＝8.0,6.0Hz,1H,CH),3.79(s,3H,OCH₃),3.34–3.25(m,2H,SO₂NCH₂),3.08(s,3H,NCH₃),2.82(dd,J＝13.4,5.8Hz,1H,PhCH),2.56(dd,J＝13.4,8.4Hz,1H,PhCH).

¹³C NMR(100MHz,DMSO-d₆)δ171.12(C＝O),167.34(C＝O),158.95,146.79,137.61,135.81,134.05,129.58,129.36(2×C),129.05(2×C),128.63(2×C),126.95,119.66,117.40,115.42,115.04(2×C),55.87,51.55,44.77,38.09,37.75.

ESI-HRMS:m/z 497.1855(M+1),1015.3449(2M+23).C₂₅H₂₈N₄O₅S[496.1780].

dissolving 6n (80mg,0.15mmol) in methanol (5mL), adding 10% Pd.C (8mg), replacing with hydrogen for three times, and stirring at room temperature for two hours under the protection of hydrogen balloon; after the reaction is finished, adding diatomite for filtration, evaporating filtrate to dryness to obtain a crude target compound, and purifying by using a silica gel preparation plate to obtain 55mg of a pure target compound (S) -2- (2- ((3-aminophenyl) sulfonamido) acetamido) -N- (4-methoxyphenyl) -N-methyl-3-phenylpropionamide (6q), a white solid, the yield of 73 percent, the melting point: 74-75 ℃.

Spectral data:

¹H NMR(400MHz,DMSO-d₆)δ8.14(d,J＝7.9Hz,1H,NH),7.63(t,J＝6.1Hz,1H,SO₂NH),7.27–7.11(m,4H,Ph-H),7.08–6.90(m,5H,Ph-H),6.90–6.81(m,3H,Ph-H),6.79–6.71(m,1H,Ph-H),5.58(s,2H,NH₂),4.41(q,J＝7.9Hz,1H,CH),3.79(s,3H,OCH₃),3.35–3.23(m,2H,SO₂NCH₂),3.08(s,3H,NCH₃),2.82(dd,J＝13.3,5.7Hz,1H,PhCH),2.58(dd,J＝13.4,8.5Hz,1H,PhCH).

¹³C NMR(100MHz,DMSO-d₆)δ171.17(C＝O),167.40(C＝O),158.96,149.79,140.98,137.61,135.80,129.96,129.38(2×C),129.07,128.63(2×C),126.95,117.69,115.05(2×C),113.64,111.55(2×C),55.87,51.53,45.37,38.08,37.76.

ESI-HRMS:m/z 497.1855(M+1).C₂₅H₂₈N₄O₅S[496.1780].

example 7 in vitro anti-HIV-1 Activity test (TZM-bl cells) of Compounds of interest

The principle is as follows: luciferase reporter Gene experiments (nef Gene deleted HIV-1NL4-3)

The test method comprises the following steps:

anti-HIV-1 infection assay in TZM-bl cells

The inhibitory activity of a compound against HIV-1 infection was determined as the degree of decrease in the expression level of luciferase gene following a single round of viral infection of TZM-bl cells. Briefly, 800TCID was used in the presence of varying concentrations of compounds (6a-q and PF-74)₅₀The virus of (NL4-3) infects TZM-bl cells. After 1 day of infection, the culture medium was removed and 100. mu.L of BrightGlo reagent (Promega, San Luis Obispo, Calif.) was added to each well and its fluorescence activity was measured using a Victor 2 luminometer. Effective concentration of compound (EC) for inhibiting HIV-1 strain₅₀) Defined as the concentration that results in a 50% decrease in luciferase activity (relative light units) compared to the virus control wells.

Cytotoxicity assays

Cytotoxicity of the synthesized compounds was determined using the CytoTox-Glo fluorescent cytotoxicity kit (purchased from Promega). TZM-bl cells were cultured for 1 day in the presence of different concentrations of compounds (6a-q and PF-74), as determined in parallel with the anti-HIV-1 activity assay. The cytotoxicity (CC) of the tested target compound is then determined according to the procedure required by the kit₅₀) I.e., the concentration of the compound of interest required to reduce cell survival by 50%.

TABLE 1 phenylalanine derivatives containing in part N- (2-oxoethyl) benzenesulfonamide anti-HIV-1 Activity, toxicity and selection index (TZM-bl cells)

^aEC₅₀: concentration of compound that protects 50% of HIV-1 infected cells from cytopathic effects;

^bCC₅₀: (ii) concentration of compound that causes lesions in 50% of cells not infected with HIV-1;

^cand (6) SI: coefficient of selectivity, CC₅₀/EC₅₀The ratio of (A) to (B);

PF-74: a class of HIV-1 capsid protein inhibitors has been reported as positive controls.

And (4) experimental conclusion analysis: as shown in Table 1, the newly synthesized N- (2-oxoethyl) benzenesulfonamide-containing phenylalanine derivatives of the present invention exhibited significant anti-HIV-1 activity. For example, EC of the target compounds 6a, 6b, 6g, 6k, 6o₅₀In the range of 5.61-6.81. mu.M, wherein the anti-HIV-1 activity (EC) of the target compound 6k₅₀＝5.61±1.54μM,CC₅₀>40.04) is particularly prominent, and has value for further research.

Claims

1. Phenylalanine derivatives containing N- (2-oxoethyl) benzenesulfonamide, characterized in that the compound is one of the following:

2. the process for preparing a phenylalanine derivative containing N- (2-oxoethyl) benzenesulfonamide according to claim 1, comprising the steps of: generating an intermediate 2 with Boc-L-phenylalanine 1 as an initial raw material and dichloromethane as a reaction solvent through an amide condensation reaction and N-methyl-4-aminoanisole; then the intermediate 2 is dissolved in a proper amount of dichloromethane, and Boc groups are removed under the action of trifluoroacetic acid to obtain an intermediate 3; then, carrying out amide condensation reaction on the intermediate 3 and N-Boc-glycine to obtain an intermediate 4; then dissolving the intermediate 4 in a proper amount of dichloromethane solution, and removing Boc group under the action of trifluoroacetic acid to obtain an intermediate 5; finally, the intermediate 5 and the corresponding substituted benzene sulfonyl chloride undergo sulfonylation reaction to obtain a target compound (6 a-n); further hydrogenating and reducing the compound (6e, m, n) to obtain a target compound (6 o-q);

the synthetic route is as follows:

reagents and conditions: (i) n-methyl-4-aminoanisole, 1H-benzotriazole-1-yloxytripyrrolidinyl hexafluorophosphate, N, N-diisopropylethylamine and dichloromethane are added, and the temperature is changed to room temperature at 0 ℃; (ii) trifluoroacetic acid, dichloromethane, room temperature; (iii) N-Boc-glycine, O- (7-azabenzotriazol-1-yl) -N, N, N ', N' -tetramethyluronium hexafluorophosphate, N, N-diisopropylethylamine and dichloromethane are stirred at 0 ℃ to room temperature; (iv) trifluoroacetic acid, dichloromethane, room temperature; (v) correspondingly substituted benzene sulfonyl chloride, triethylamine and dichloromethane are cooled to room temperature at 0 ℃; (vi) h₂10% Pd · C, dichloromethane/methanol, room temperature;

wherein R is: H. 4-F, 3-F, 2-F, 4-Cl, 4-Br, 4-methoxy, 4-methyl, 3, 5-dimethyl, 2,4, 6-trimethyl, 4-nitro, 3-nitro, 2,4, 6-triisopropyl;

3. The method for preparing the phenylalanine derivative containing N- (2-oxoethyl) benzenesulfonamide according to claim 2, comprising the following steps:

(3) adding N-Boc-glycine and O- (7-azabenzotriazole-1-yl) -N, N, N ', N' -tetramethylurea hexafluorophosphate into dichloromethane, and stirring for 1h under an ice-bath condition; then adding the intermediate 3 and N, N-diisopropylethylamine into the solution, removing the ice bath, and stirring at room temperature for 6 h; after the reaction is finished, filtering, decompressing and evaporating the solvent, and separating by silica gel column chromatography to obtain an intermediate 4;

(4) adding the intermediate 4 into dichloromethane, slowly adding trifluoroacetic acid into the dichloromethane under the condition of ice bath and stirring, then removing the ice bath, transferring the mixture to room temperature, and monitoring by TLC; after the reaction is finished, evaporating the solvent under reduced pressure, adding a saturated sodium bicarbonate solution to adjust the pH of the reaction solution to 7, and then adding a dichloromethane solution for extraction; separating and taking an organic phase, washing the organic phase for 3 times by using a saturated sodium chloride solution, drying the organic phase by using anhydrous sodium sulfate, filtering, and evaporating the solvent to dryness under reduced pressure to obtain an intermediate 5;

(5) adding the intermediate 5 and triethylamine into dichloromethane, slowly adding the corresponding substituted benzene sulfonyl chloride into the dichloromethane under the condition of ice bath and stirring, then removing the ice bath, transferring the mixture to room temperature, and monitoring by TLC; after the reaction is finished, adding saturated sodium chloride solution, extracting by dichloromethane, separating and taking an organic phase, drying by using anhydrous sodium sulfate, filtering, evaporating the solvent by decompression, separating by silica gel column chromatography to obtain a crude product of the target compound, and recrystallizing by ethyl acetate to obtain a pure product (6a-n) of the target compound;

(6) dissolving the compound (6e, m, n) in methanol and dichloromethane, adding 10% Pd.C, replacing with hydrogen for three times, and stirring at room temperature for two hours under the protection of a hydrogen balloon; after the reaction is finished, adding diatomite for filtration, evaporating the filtrate to dryness to obtain a crude product of the target compound, and purifying by a silica gel preparation plate to obtain a pure product (6o-q) of the target compound.

4. The use of the phenylalanine derivative containing N- (2-oxoethyl) benzenesulfonamide according to claim 1 in the preparation of medicaments for the treatment and prevention of aids.

5. An anti-HIV pharmaceutical composition comprising a phenylalanine derivative containing N- (2-oxoethyl) benzenesulfonamide according to claim 1 or a pharmaceutically acceptable salt thereof and one or more pharmaceutically acceptable carriers or excipients.