CN108033952B - Phenylalanine derivative and the preparation method and application thereof containing triazole ring - Google Patents

Phenylalanine derivative and the preparation method and application thereof containing triazole ring Download PDF

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CN108033952B
CN108033952B CN201810088488.6A CN201810088488A CN108033952B CN 108033952 B CN108033952 B CN 108033952B CN 201810088488 A CN201810088488 A CN 201810088488A CN 108033952 B CN108033952 B CN 108033952B
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azide
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triazole ring
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CN108033952A (en
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展鹏
武高禅
刘新泳
李国雄
康东伟
俞霁
孙林
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Shandong University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/14—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/04—1,2,3-Triazoles; Hydrogenated 1,2,3-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D405/00—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom
    • C07D405/02—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings
    • C07D405/04—Heterocyclic compounds containing both one or more hetero rings having oxygen atoms as the only ring hetero atoms, and one or more rings having nitrogen as the only ring hetero atom containing two hetero rings directly linked by a ring-member-to-ring-member bond

Abstract

The present invention relates to the phenylalanine derivatives and the preparation method and application thereof containing triazole ring.The compound has structure shown in Formulas I.The invention further relates to the pharmaceutical compositions containing Formulas I structural compounds.Composition the present invention also provides above compound and containing one or more such compounds treats and prevents the application in AIDS-treating medicine in preparation.

Description

Phenylalanine derivative and the preparation method and application thereof containing triazole ring
Technical field
The invention belongs to organic compound synthesis and medical applications technical field, and in particular to a kind of benzene containing triazole ring Alanine derivatives and the preparation method and application thereof.
Background technique
AIDS (Acquired Immune Deficiency Syndrome, AIDS) is mainly by human immune deficiency The weight of human life and health is endangered caused by virus I-type (Human Immunodeficiency Virus Type 1, HIV-1) Big communicable disease.Currently, difference of the drug of the treatment AIDS of clinical application according to action target, is broadly divided into: reversing Transcriptase inhibitors, four major class of protease inhibitors, integrase inhibitor and fusion inhibitor." efficient anti-reverse transcription therapy " (Highly Active Antiretroviral Therapy, HAART) largely extends the life span of patient, Improve the life quality of patient, but resistance problems, poisonous side effect of medicine, latent infection and prolonged administration of drugs great number The problems such as expense, greatly reduces the effect of therapy, limits the application of the therapy, so force researcher research and develop novel targets, The anti-AIDS drug of new mechanism, new construction.
HIV-1 capsid is to assemble to be formed after obtaining capsid protein unit by a part shearing of Gag precursor protein.Not During mature virion is changed into mature virion, capsid protein is assembled into capsid, by viral RNA and and nuclear phase In the albumen (reverse transcriptase, protease, integrase etc.) of pass is wrapped in, mature HIV-1 virion is formed.Mature virus Particle has infectiousness just now, can carry out the next round duplication of virus.In recent years, as researcher is to capsid protein structure It understands in depth, the relevant information of crystal structure is also reported successively.Thus, the capsid protein of HIV-1 can be used as new resist The action target spot of HIV-1.
Pfizer company obtains to significantly inhibit the compound PF- of HIV-1 duplication by the high flux screening of compound library 74, structure-activity relationship is carried out to it and Mechanism Study shows this kind of compound by combining HIV-1 capsid protein, and then interference disease The shelling of poison and the process for forming infectious particles.Although PF-74 structure novel, mechanism are unique, target spot is clear, PF-74 phase The curative effect of medication of anti-HIV-1 for having listed at present is lower, and activity is in micromole's rank.Therefore, highly efficient clothing is researched and developed Glutelin inhibitor becomes direction noticeable in the field of anti-AIDS drug research and development in recent years.
Summary of the invention
In view of the deficiencies of the prior art, the present invention provides a kind of phenylalanine derivative containing triazole ring and its preparations Method, active ingredients result and its application the present invention also provides above compound as HIV-1 capsid protein inhibitor.
Technical scheme is as follows:
1. the phenylalanine derivative containing triazole ring
Containing the phenylalanine derivative of triazole ring or its pharmaceutically acceptable salt, ester or prodrug, there is general formula I institute The structure shown:
Wherein,
M=0,1,2,3；
N=0,1,2,3；
R1Are as follows: H, OH, C1-C6Alkyl, OC1-C6Alkyl, C2-C6Alkenyl, C3-C6Naphthenic base, OC3-C6Naphthenic base, substituted benzene Ring, trifluoromethyl, replaces naphthalene nucleus, various substituted hexa-member heterocycles or various substituted five-ring heterocycles at substituted benzyl；
R2Are as follows: H, F, Cl, Br, CF3；
R are as follows: C1-C6Alkyl, OC1-C6Alkyl, C2-C6Alkenyl, C3-C6Naphthenic base, OC3-C6Naphthenic base, takes substituted benzene ring For naphthalene nucleus, replace fragrant sulfone, replace aromatic sulfide, replace fragrant sulfoxide, various substituted hexa-member heterocycles, various substituted five-ring heterocycles, It is various substituted hexa-atomic and five-ring heterocycles, various substituted hexa-atomic and hexa-member heterocycles, various substituted five yuan and five-ring heterocycles, each The benzo five-membered heterocycle or various substituted benzo hexa-member heterocycles that kind replaces.
It is preferred according to the present invention,
N=0,
R1For OCH3,
(1) m=1, R are the substituted benzene ring with a-d general formula；
Wherein, R3For Cl, Me, CN, NO2；X is S, SO, SO2；
(2) m=0, R are Z group, and Z is that Zidovudine removes the group after nitrine, the phenyl or benzene that methoxycarbonyl group replaces And [d] [1,3] dioxolyl group.
According to the present invention it is further preferred that the phenylalanine derivative containing triazole ring is one of following compounds:
Heretofore described " pharmaceutically acceptable salt " refer in reliable medicine range of value, the salt of compound Class is suitable for being in contact with people or compared with the tissue of lower animal without unsuitable toxicity, stimulation and allergic reaction etc., has suitable Reasonable income and risk ratio, usually water or oil are soluble or dispersible, and are effectively used for its expected purposes. Including pharmaceutically acceptable acid-addition salts and pharmaceutically acceptable base addition salts, be herein can do expected purposes and with The chemical property of compound of formula I is compatible.The list of suitable salt is referring to S.M.Birge etc., J.Pharm.Sci., 1977, and 66, 1-19 pages.
Heretofore described " prodrug " refers to pharmaceutically acceptable derivates, so as to the resulting biology of these derivatives Transformation product is the active medicine as defined in compound of formula I.
2. the preparation method of the phenylalanine derivative containing triazole ring
The preparation method of phenylalanine derivative containing triazole ring, steps are as follows: with substituted Boc-L- phenylalanine Intermediate B is generated with substituted aniline by amide condensed reaction in dichloromethane solution for starting material；Then intermediate B It is dissolved in q. s. methylene chloride solution, Boc group is sloughed under the action of trifluoroacetic acid, obtain intermediate C；Then, intermediate Body C and propiolic acid, tetrolic acid, pentinoic acid or hexynic acid occur amide condensed to react to obtain the key intermediate D with alkynes segment； Finally, nitrine-alkynes that intermediate D and azide under the conditions of sodium ascorbate and cupric sulfate pentahydrate, are catalyzed by Cu (I) Husigen-Click cycloaddition reaction generates target product I.
Synthetic route is as follows:
Reagent and condition: (i) substituted aniline, 1H- benzotriazole -1- base oxygen tripyrrole alkyl hexafluorophosphate, N, N- bis- Wopropyl ethyl amine, methylene chloride, 0 DEG C, room temperature；(ii) trifluoroacetic acid, methylene chloride, room temperature；(iii) O- (7- azepine benzo three Azoles -1- base)-N, N, N', N'- tetramethylurea hexafluorophosphate, n,N-diisopropylethylamine, methylene chloride, 0 DEG C, room temperature；(iv) Sodium ascorbate, cupric sulfate pentahydrate, water/tetrahydrofuran, azide, 30-65 DEG C.
Wherein, n, m, R, R1、R2With shown in above-mentioned general formula I.
The substituted aniline is N- methyl -4- aminoanisole, N- methyl -4- aminobenzene methanol, N- methyl -4- amino Phenol.
The azide is substituted benzene ring azide, replaces naphthalene nucleus azide, replace fragrant sulfone, replace fragrant sulphur Ether replaces fragrant sulfoxide, various substituted hexa-member heterocycle azide, various substituted five-ring heterocycles azide, various substitutions Hexa-atomic and five-ring heterocycles azide, various substituted hexa-atomic and hexa-member heterocycle azide, substituted five yuan and five various Circle heterocyclic ring azide, various substituted benzo five-membered heterocycle azide or various substituted benzo hexa-member heterocycle Azides Object.
Room temperature of the present invention is 20-30 DEG C.
It is preferred according to the present invention, the preparation method of the phenylalanine derivative containing triazole ring, the specific steps are as follows:
(1) starting material A is added in dichloromethane solution, 1H- benzene is then added under condition of ice bath into this solution And triazol-1-yl oxygen tripyrrole alkyl hexafluorophosphate, stir 0.5h；Then to N, N- diisopropylethylamine are added in reaction solution And substituted aniline, TLC monitoring, to end of reaction, then saturated sodium bicarbonate is added in evaporating solvent under reduced pressure into bottle in residue Solution, ethyl acetate extraction；Divide and take organic layer, 1N HCl solution is added, water phase is extracted with ethyl acetate；Merge organic layer, adds Saturated common salt water washing, organic phase are dry with anhydrous sodium sulfate；Filtering, evaporated under reduced pressure solvent obtain the thick of midbody compound B Product；
(2) the crude Compound B that upper step obtains is added in dichloromethane solution, is then added into this solution excessive Trifluoroacetic acid stirs 8-9h under room temperature；Then the pH=9 that reaction solution is adjusted with saturated sodium bicarbonate solution, adds two The extraction of chloromethanes solution；Merging organic layer, saturated common salt water washing 3 times；Anhydrous sodium sulfate is dry；Filtering, evaporated under reduced pressure solvent； The isolated intermediate C sterling of silica gel column chromatography；
(3) in the dichloromethane solution for being added to end group acetylenic acid, O- (7- azepine benzo three is then added into this solution Azoles -1- base)-N, N, N', N'- tetramethylurea hexafluorophosphate, ice bath stirring 1h；Intermediate C and N, N- are added into this solution After removing ice bath, 7-8h is stirred at room temperature in diisopropylethylamine；Reaction is finished, evaporating solvent under reduced pressure, is then added in residue into bottle Enter saturated sodium bicarbonate solution, ethyl acetate extraction；Divide and take organic layer, 1N HCl solution, ethyl acetate extraction is added；It is associated with Machine layer, adds saturated common salt water washing, and organic phase is dry with anhydrous sodium sulfate；Filtering, evaporated under reduced pressure solvent；Silica gel column chromatography separation Obtain intermediate D sterling；
(4) key intermediate D and azide are added to the mixed solvent of tetrahydrofuran and water that volume ratio is 1:1 In；Then sodium ascorbate, cupric sulfate pentahydrate are added into this solution；This mixed solution is heated to 30-65 DEG C and is vigorously stirred 4-12h；Then, suitable water is added into reaction solution, is extracted with ethyl acetate；Divide and take organic layer, anhydrous sodium sulfate is dry；It crosses Filter, evaporated under reduced pressure solvent；Silica gel column chromatography separation；Ethyl acetate/petroleum ether or methylene chloride/n-hexane are recrystallized to give three Azole target compound I.
3. the application of the phenylalanine derivative containing triazole ring
The invention discloses the phenylalanine derivative Anti-HIV-1 Active the selection result containing triazole ring and its as HIV-1 Inhibitor is applied for the first time.Being experimentally confirmed the phenylalanine derivative of the invention containing triazole ring can be used as HIV-1 inhibition Agent is used to prepare anti-AIDS drug.The present invention also provides the applications in above compound inverase.
The Anti-HIV-1 Active and toxicity test of target compound
The anti-of cellular level has been carried out to a kind of phenylalanine derivative containing triazole ring synthesized according to the method described above HIV-1 activity and toxotest, their Anti-HIV-1 Active and toxicity data are listed in Table 1 below, with the inhibition of existing capsid protein Agent PF-74 is positive control.
The newly synthesized phenylalanine derivative containing triazole ring of the present invention shows significant Anti-HIV-1 Active.For example, changing Object WG1, WG2, WG3, WG5, WG11, WG12, WG13, WG16, WG19 Anti-HIV-1 Active are closed within the scope of 4.33-14.93 μM, With positive control PF-74 activity (EC50=5.95 ± 1.32 μM, CC50> 70.50, SI > 11.85) more excellent or suitable, wherein chemical combination Anti-HIV-1 Active (the EC of object WG1650=4.33 ± 0.83 μM, CC50> 57.74, SI > 13.33) it is especially prominent, have further The value of research.
A kind of phenylalanine derivative containing triazole ring of the invention can be used as HIV-1 inhibitor application.Specifically, Anti-AIDS drug is used to prepare as HIV-1 inhibitor.
A kind of anti-HIV-1 medicines composition, including a kind of phenylalanine derivative containing triazole ring and one of the invention Kind or a variety of pharmaceutically acceptable carriers or excipient.
Phenylalanine derivative and preparation method thereof the present invention provides one kind containing triazole ring, the present invention also provides Part of compounds Anti-HIV-1 Active the selection result and its applying in antiviral field for the first time.Test proves that the present invention A kind of phenylalanine derivative containing triazole ring can be used as HIV-1 inhibitor and apply and there is very high application value.Tool It says to body, is used to prepare anti-AIDS drug as HIV-1 inhibitor.
Specific embodiment
Facilitate to understand the present invention by following embodiments, but the contents of the present invention cannot be limited.
Synthetic route involved in embodiment is as follows:
Embodiment 1: key intermediate (S)-N- (1- (4- methoxyphenyl) (methyl) amino) -1- carbonyl -3- phenyl -2- Base) propine amide (4) preparation
The anhydrous methylene chloride that starting material Boc-L- phenylalanine (1) (8.75mmol, 2.3g) is added to 15mL is molten In liquid, 1H- benzotriazole -1- base oxygen tripyrrole alkyl hexafluorophosphate (10.9mmol, 5.7g) then is added into this solution. 0.5h is stirred under condition of ice bath, and n,N-diisopropylethylamine (21.87mmol, 3.61mL) and N- methyl -4- amino is then added Methyl phenyl ethers anisole (7.29mmol, 1.0g), removes ice bath, 12h is stirred at room temperature.To end of reaction, evaporating solvent under reduced pressure, then into bottle Saturated sodium bicarbonate solution, ethyl acetate extraction are added in residue；Divide and take organic layer, 1N HCl solution, ethyl acetate is added Extraction；Merge organic layer, add saturated common salt water washing, organic phase is dry with anhydrous sodium sulfate；Filtering, evaporated under reduced pressure solvent obtain Midbody compound tert-butyl-(S)-(1- ((4- methoxyphenyl) (methyl) amino) -1- oxo -3- phenylpropyl -2- base) ammonia The crude product 2.63g of carbamate (2), yellow oil, yield 94%,1H NMR(400MHz,DMSO-d6) δ 7.21 (d, J= 8.4Hz, 3H), 7.15 (d, J=7.1Hz, 2H), 7.02 (d, J=8.4Hz, 2H), 6.85-6.75 (m, 2H), 4.15 (q, J= 5.4Hz,1H),3.80(s,3H),3.12(s,3H),2.81–2.54(m,2H),1.30(s,9H)；
The crude product 2 (2.63g, 6.84mmol, 1.0eq) that upper step obtains is added in 30mL methylene chloride, then to this Trifluoroacetic acid (34.2mmol, 5.0eq) is added in solution, 8-9h is stirred at room temperature.Then it is adjusted with saturated sodium bicarbonate solution anti- The pH=9 of liquid is answered, dichloromethane solution extraction is added；Merging organic layer, saturated common salt water washing 3 times；Anhydrous sodium sulfate is dry； Filtering is concentrated under reduced pressure, the isolated intermediate of silica gel column chromatography (S) -2- amino-N- (4- methoxyphenyl)-N- methyl -3- benzene The sterling of propionamide (3), yellow oil, yield 84%.1H NMR(400MHz,DMSO-d6)δ7.34–7.15(m,3H), 6.90 (s, 6H), 3.77 (s, 3H), 3.35 (t, J=6.9Hz, 1H), 3.06 (s, 3H), 2.76 (dd, J=12.9,6.8Hz, 1H), 2.46 (dd, J=12.9,7.1Hz, 1H)
Propiolic acid (4.22mmol, 0.3g) is added in 15mL anhydrous methylene chloride solution, then under condition of ice bath Addition O- (7- azepine benzo triazol-1-yl)-N, N, N' into this solution, N'- tetramethylurea hexafluorophosphate (5.28mmol, 2.0g), stir 1h under condition of ice bath, then in this solution be added n,N-diisopropylethylamine (7.03mmol, 1.16mL) and Intermediate 3 removes ice bath, stirs 7-8h under room temperature；To end of reaction, evaporating solvent under reduced pressure, the then residue into bottle Middle addition saturated sodium bicarbonate solution, ethyl acetate extraction；Divide and take organic layer, 1N HCl solution, ethyl acetate extraction is added；It closes And organic layer, add saturated common salt water washing, organic phase is dry with anhydrous sodium sulfate；Filtering, evaporated under reduced pressure solvent；Silica gel column chromatography Isolated intermediate (S)-N- (1- (4- methoxyphenyl) (methyl) amino) -1- carbonyl -3- phenyl -2- base) propine amide (4) sterling, yellow oily liquid, yield 38%.1H NMR(400MHz,DMSO-d6) δ 9.16 (d, J=7.8Hz, 1H), 7.17 (td, J=7.0,4.5Hz, 5H), 7.00 (d, J=8.9Hz, 2H), 6.85-6.82 (m, 2H), 4.45 (ddd, J=9.7, 7.7,4.5Hz,1H),3.79(s,3H),3.12(s,3H),2.91–2.71(m,2H),2.69(s,1H).。
The synthesis of 2. target product WG1-WG20 of embodiment
The azide (0.357mmol, 1.2eq) of key intermediate 4 (0.297mmol, 1eq) and preparation is added to four In the mixed solvent (v/v=1:1,10mL) of hydrogen furans and water.Then sodium ascorbate is added into this solution (0.0891mmol, 17.65mg) and cupric sulfate pentahydrate (0.0297mmol, 7.43mg).This mixed solution is heated to 30-65 DEG C simultaneously It is vigorously stirred 4-12h.Then, suitable water is added into reaction solution, is extracted with ethyl acetate；Divide and takes organic layer, anhydrous slufuric acid Sodium is dry；Filtering, evaporated under reduced pressure solvent；Silica gel column chromatography separation；Ethyl acetate/petroleum ether or methylene chloride/n-hexane weight Crystallization obtains target compound WG1-WG20.
Azide used is Zidovudine.Product is white solid, yield: 50%, 143-145 DEG C of fusing point.
1H NMR(400MHz,DMSO-d6) δ 11.37 (s, 1H), 8.73 (s, 1H), 8.35 (d, J=8.1Hz, 1H), 7.89-7.76 (m, 1H), 7.18 (dt, J=15.1,8.1Hz, 5H), 7.02 (d, J=8.4Hz, 2H), 6.95-6.80 (m, 2H), 6.42 (t, J=6.6Hz, 1H), 5.43 (dt, J=8.6,5.5Hz, 1H), 5.28 (t, J=5.2Hz, 1H), 4.70 (q, J =7.3Hz, 1H), 4.23 (q, J=4.0Hz, 1H), 3.81 (s, 3H), 3.74-3.54 (m, 2H), 3.13 (s, 3H), 2.91 (d, J=7.0Hz, 2H), 2.71 (dq, J=35.8,6.6,5.9Hz, 2H), 1.81 (s, 3H)13C NMR(100MHz,DMSO-d6)δ 171.25,164.19,159.52,159.09,150.89,142.69,137.98,136.72,135.92,129.35,129.25, 128.62,126.90,126.69,115.22,110.11,84.73,84.29,61.09,60.06,55.93,51.73,37.90, 37.60,37.29,12.73.ESI-MS:C30H33N7O7,Exact Mass:603.24,m/z 604.5(M+1)+.
Azide used is 3- (azido-methyl) cyanophenyl.Product is white solid, yield: 62%, fusing point 168-170 ℃。
1H NMR(400MHz,DMSO-d6) δ 8.65 (s, 1H), 8.35 (d, J=8.0Hz, 1H), 7.90-7.81 (m, 2H), 7.62 (dt, J=15.3,7.8Hz, 2H), 7.17 (dt, J=13.8,7.6Hz, 5H), 7.01 (d, J=8.5Hz, 2H), 6.93- 6.82 (m, 2H), 5.72 (s, 2H), 4.67 (q, J=7.3Hz, 1H), 3.81 (s, 3H), 3.12 (s, 3H), 2.89 (d, J= 7.0Hz,2H).13C NMR(100MHz,DMSO-d6)δ171.24,159.50,159.08,142.82,137.97,135.93, 133.45,132.59,132.25,129.35,129.23,128.60,127.37,126.89,118.85,115.20,112.22, 55.92,52.60,51.73,37.88,37.31.ESI-MS:C28H26N6O3,Exact Mass:494.21,m/z 495.4(M+ 1)+.
Azide used is 4- (azido-methyl) cyanophenyl.Product is white solid, yield: 45%, fusing point 190-192 ℃。
1H NMR(400MHz,DMSO-d6) δ 8.65 (s, 1H), 8.37 (d, J=8.0Hz, 1H), 7.91-7.81 (m, 2H), 7.47 (d, J=8.0Hz, 2H), 7.17 (dt, J=13.7,7.6Hz, 5H), 7.07-6.96 (m, 2H), 6.94-6.82 (m, 2H), 5.77 (s, 2H), 4.68 (q, J=7.2Hz, 1H), 3.81 (s, 3H), 3.13 (s, 3H), 2.90 (d, J=7.0Hz, 2H) .13C NMR(100MHz,DMSO-d6)δ171.26,159.53,159.08,142.82,141.51,138.01,135.92, 133.25,129.34,129.20,128.61,127.54,126.89,118.97,115.20,111.51,55.92,52.90, 51.80,37.88,37.20.ESI-MS:C28H26N6O3,Exact Mass:494.21,m/z 495.4(M+1)+.
Azide 2- (azido-methyl) cyanophenyl used.Product is faint yellow solid, yield: 58%, 68-70 DEG C of fusing point.
1H NMR(400MHz,DMSO-d6) δ 8.62 (s, 1H), 8.39 (d, J=8.0Hz, 1H), 7.93 (dd, J=7.7, 1.3Hz, 1H), 7.77-7.70 (m, 1H), 7.61-7.55 (m, 1H), 7.38 (d, J=7.8Hz, 1H), 7.17 (dt, J= 13.7,7.5Hz, 5H), 7.01 (d, J=8.5Hz, 2H), 6.91-6.84 (m, 2H), 5.87 (s, 2H), 4.67 (q, J= 7.2Hz, 1H), 3.81 (s, 3H), 3.13 (s, 3H), 2.90 (d, J=6.9Hz, 2H)13C NMR(100MHz,DMSO-d6)δ 171.25,159.47,159.08,142.63,138.84,137.99,135.92,134.36,133.91,129.94,129.79, 129.35,129.25,128.60,127.65,126.89,117.38,115.20,111.66,55.93,51.79,51.76, 37.89,37.24.ESI-MS:C28H26N6O3,Exact Mass:494.21,m/z 495.4(M+1)+.
Azide 1- (azido-methyl) -2- toluene used.Product is white solid, yield: 70%, 60-62 DEG C of fusing point.
1H NMR(400MHz,DMSO-d6) δ 8.49 (s, 1H), 8.35 (d, J=8.0Hz, 1H), 7.31-7.12 (m, 8H), 7.08 (d, J=7.5Hz, 1H), 7.00 (d, J=8.4Hz, 2H), 6.92-6.82 (m, 2H), 5.66 (s, 2H), 4.66 (q, J= 7.4Hz,1H),3.80(s,3H),3.12(s,3H),2.81(m,2H),2.30(s,3H).13C NMR(100MHz,DMSO-d6)δ 171.28,159.56,159.07,142.56,137.98,136.76,135.93,134.20,130.94,129.35,129.24, 129.12,128.93,128.60,127.04,126.89,126.79,115.19,55.92,51.76,51.68,37.88, 37.27,19.09.ESI-MS:C28H29N5O3,Exact Mass:483.23,m/z 484.5(M+1)+.
Azide 1- (azido-methyl) -3- toluene used.Product is yellow solid, yield: 30%, 58-60 DEG C of fusing point.
1H NMR(400MHz,DMSO-d6) δ 8.59 (s, 1H), 8.34 (d, J=8.0Hz, 1H), 7.23-7.12 (m, 8H), 7.01 (d, J=8.2Hz, 3H), 6.88 (d, J=6.8Hz, 2H), 5.60 (s, 2H), 4.67 (q, J=6.0Hz, 1H), 3.81 (s, 3H), 3.12 (d, J=4.9Hz, 3H), 2.89 (d, J=7.1Hz, 2H), 2.29 (s, 3H)13C NMR(100MHz,DMSO- d6)δ171.28,159.56,159.08,142.57,137.97,136.77,135.93,134.19,130.94,129.35, 129.23,129.13,128.93,128.60,127.03,126.89,126.79,115.19,55.91,51.75,51.69, 37.88,37.31,19.09.ESI-MS:C28H29N5O3,Exact Mass:483.23,m/z 484.5(M+1)+.
Azide 1- (azido-methyl) -4- toluene used.Product is yellow solid, yield: 55%, 63-65 DEG C of fusing point.
1H NMR(400MHz,DMSO-d6) δ 8.56 (s, 1H), 8.32 (d, J=8.0Hz, 1H), 7.36-7.08 (m, 9H), 7.00 (d, J=8.4Hz, 2H), 6.92-6.83 (m, 2H), 5.58 (s, 2H), 4.66 (q, J=7.3Hz, 1H), 3.80 (s, 3H), 3.12 (s, 3H), 2.88 (d, J=7.1Hz, 2H), 2.28 (s, 3H)13C NMR(100MHz,DMSO-d6)δ171.27, 159.58,159.07,142.67,138.12,137.98,135.92,133.09,129.80,129.34,129.24,128.60, 128.47,126.90,115.19,55.91,53.34,51.73,37.88,37.27,21.17.ESI-MS:C28H29N5O3, Exact Mass:483.23,m/z484.5(M+1)+.
Azide used is 1- (azido-methyl) -2- chlorobenzene.Product is yellow solid, yield: 60%, fusing point 62-64 ℃。
1H NMR(400MHz,DMSO-d6) δ 8.56 (s, 1H), 8.38 (d, J=8.0Hz, 1H), 7.54 (dd, J=7.6, 1.7Hz, 1H), 7.40 (pd, J=7.5,1.7Hz, 2H), 7.29-7.11 (m, 6H), 7.01 (d, J=8.5Hz, 2H), 6.94- 6.75 (m, 2H), 5.76 (s, 2H), 4.67 (q, J=7.3Hz, 1H), 3.80 (s, 3H), 3.12 (s, 3H), 2.89 (d, J= 7.0Hz,2H).13C NMR(100MHz,DMSO-d6)δ171.28,159.52,159.08,142.50,137.99,135.93, 133.30,133.12,131.07,130.87,130.15,129.35,129.24,128.60,128.26,127.45,126.89, 115.19,55.92,51.78,51.41,37.88,37.25.ESI-MS:C27H26ClN5O3,Exact Mass:503.17,m/z 504.3(M+1)+.
Azide used is 1- (azido-methyl) -3- chlorobenzene.Product is white solid, yield: 65%, fusing point 288- 290℃。
1H NMR(400MHz,DMSO-d6) δ 8.64 (s, 1H), 8.36 (d, J=8.0Hz, 1H), 7.42 (dd, J=6.0, 2.9Hz, 3H), 7.37-7.25 (m, 1H), 7.23-7.10 (m, 5H), 7.01 (d, J=8.4Hz, 2H), 6.93-6.80 (m, 2H), 5.67 (s, 2H), 4.67 (q, J=7.3Hz, 1H), 3.80 (s, 3H), 3.12 (s, 3H), 2.89 (d, J=7.0Hz, 2H) .13C NMR(100MHz,DMSO-d6)δ171.26,159.54,159.07,142.77,138.44,138.00,135.92, 133.78,131.24,129.35,129.25,128.75,127.27,127.18,126.89,115.19,55.92,52.75, 51.78,37.88,37.24.ESI-MS:C27H26ClN5O3,Exact Mass:503.17,m/z 504.3(M+1)+.
Azide used is 1- (azido-methyl) -4- chlorobenzene.Product is white solid, yield: 50%, fusing point 172- 174℃。
1H NMR(400MHz,DMSO-d6) δ 8.61 (s, 1H), 8.34 (d, J=8.1Hz, 1H), 7.51-7.42 (m, 2H), 7.35 (d, J=8.3Hz, 2H), 7.26-7.09 (m, 5H), 7.01 (d, J=8.8Hz, 2H), 6.93-6.81 (m, 2H), 5.65 (s, 2H), 4.67 (q, J=7.3Hz, 1H), 3.80 (s, 3H), 3.12 (s, 3H), 2.89 (d, J=7.0Hz, 2H)13C NMR (100MHz,DMSO-d6)δ171.26,159.54,159.08,142.75,137.98,135.93,135.08,133.47, 130.40,129.34,129.28,129.24,128.60,127.16,126.89,115.20,55.92,52.73,51.75, 37.88,37.26.ESI-MS:C27H26ClN5O3,Exact Mass:503.17,m/z 504.3(M+1)+.
Azide used is 5- nitrine benzo [d] [1,3] dioxole.Product is white solid, yield: 65%, 136-138 DEG C of fusing point.
1H NMR(400MHz,DMSO-d6) δ 9.10 (s, 1H), 8.42 (d, J=8.0Hz, 1H), 7.53 (d, J=2.2Hz, 1H), 7.41 (dd, J=8.4,2.2Hz, 1H), 7.25-7.10 (m, 6H), 7.06-7.00 (m, 2H), 6.95-6.89 (m, 2H), 6.16 (s, 2H), 4.72 (q, J=7.2Hz, 1H), 3.81 (s, 3H), 3.14 (s, 3H), 2.94 (d, J=6.9Hz, 2H)13C NMR(100MHz,DMSO-d6)δ171.20,159.36,159.10,148.64,148.29,143.20,137.94,135.94, 131.05,129.40,129.26,128.62,126.91,125.40,115.22,114.89,109.11,102.71,55.93, 51.79,37.92,37.34.ESI-MS:C27H25N5O5,Exact Mass:499.19,m/z 500.3(M+1)+.
Azide used is 3- azidobenzoic acid methyl esters.Product is white solid, yield: 80%, fusing point 170-172 ℃。
1H NMR(400MHz,DMSO-d6) δ 9.37 (s, 1H), 8.52 (d, J=8.0Hz, 1H), 8.50-8.43 (m, 1H), 8.27-8.20 (m, 1H), 8.09 (dt, J=7.8,1.3Hz, 1H), 7.78 (t, J=8.0Hz, 1H), 7.29-7.13 (m, 5H), 7.02 (d, J=8.4Hz, 2H), 6.99-6.88 (m, 2H), 4.73 (q, J=7.2Hz, 1H), 3.92 (s, 3H), 3.82 (s, 3H), 3.15 (s, 3H), 2.95 (d, J=6.9Hz, 2H)13C NMR(100MHz,DMSO-d6)δ171.19,165.67, 159.23,159.11,143.57,137.96,136.98,136.65,135.94,131.76,131.09,130.00,129.40, 129.26,128.63,126.92,125.59,125.49,121.25,115.22,55.93,53.07,51.86,37.93, 37.34.ESI-MS:C28H27N5O5,Exact Mass:513.20,m/z 514.3(M+1)+.
Azide used is 1- azido-methyl -2- nitrobenzene.Product is yellow solid, yield: 60%, fusing point 63-65 ℃。
1H NMR(400MHz,DMSO-d6) δ 8.57 (s, 1H), 8.41 (d, J=8.0Hz, 1H), 8.16 (d, J=8.0Hz, 1H), 7.76 (t, J=7.6Hz, 1H), 7.66 (t, J=7.8Hz, 1H), 7.18 (dt, J=13.2,6.8Hz, 5H), 7.09 (d, J=7.7Hz, 1H), 7.01 (d, J=8.4Hz, 2H), 6.94-6.83 (m, 2H), 6.02 (s, 2H), 4.68 (q, J=7.2Hz, 1H), 3.81 (s, 3H), 3.13 (s, 3H), 2.91 (d, J=6.9Hz, 2H)13C NMR(100MHz,DMSO-d6)δ171.28, 159.51,159.09,148.01,142.64,138.00,135.94,134.93,130.82,130.69,130.26,129.35, 129.25,128.61,127.89,126.90,125.63,115.20,55.92,51.80,50.80,37.88,37.25.ESI- MS:C27H26N6O5,Exact Mass:514.20,m/z 515.5(M+1)+.
Azide used is 1- azido-methyl -3- nitrobenzene.Product is faint yellow solid, yield: 67%, fusing point 61- 63℃。
1H NMR(400MHz,DMSO-d6) δ 8.69 (s, 1H), 8.37 (d, J=8.0Hz, 1H), 8.25 (t, J=2.0Hz, 1H), 8.22 (d, J=8.3Hz, 1H), 7.78 (d, J=7.7Hz, 1H), 7.69 (t, J=7.9Hz, 1H), 7.18 (dd, J= 18.4,7.9Hz, 5H), 7.01 (d, J=8.4Hz, 2H), 6.92-6.83 (m, 2H), 5.83 (s, 2H), 4.67 (q, J= 7.2Hz, 1H), 3.80 (s, 3H), 3.12 (s, 3H), 2.89 (d, J=6.9Hz, 2H)13C NMR(100MHz,DMSO-d6)δ 171.24,159.50,159.08,148.37,142.83,138.11,137.98,135.93,135.23,130.94,129.34, 129.24,128.59,127.44,126.89,123.73,123.38,115.20,55.92,52.51,51.77,37.88, 37.25.ESI-MS:C27H26N6O5,Exact Mass:514.20,m/z 515.5(M+1)+.
Azide used is 1- azido-methyl -4- nitrobenzene.Product is faint yellow solid, yield: 57%, fusing point 213- 215℃。1H NMR(400MHz,DMSO-d6) δ 8.67 (s, 1H), 8.38 (d, J=8.0Hz, 1H), 8.29-8.20 (m, 2H), 7.54 (d, J=8.6Hz, 2H), 7.17 (dt, J=13.8,7.7Hz, 5H), 7.01 (d, J=8.8Hz, 2H), 6.93-6.84 (m, 2H), 5.84 (s, 2H), 4.68 (q, J=7.2Hz, 1H), 3.81 (s, 3H), 3.13 (s, 3H), 2.90 (d, J=7.0Hz, 2H).13C NMR(100MHz,DMSO-d6)δ171.25,159.51,159.09,147.77,143.44,142.85,137.99, 135.93,129.53,129.34,129.24,128.61,127.60,126.89,124.42,115.21,55.93,52.64, 51.78,37.88,37.25.ESI-MS:C27H26N6O5,Exact Mass:514.20,m/z 515.4(M+1)+.
Azide used is 2- azido-methyl naphthalene.Product is white solid, yield: 65%, 72-74 DEG C of fusing point.
1H NMR(400MHz,DMSO-d6) δ 8.66 (s, 1H), 8.34 (d, J=8.0Hz, 1H), 7.93 (dd, J=8.9, 4.9Hz, 3H), 7.87 (s, 1H), 7.54 (dd, J=6.5,3.1Hz, 2H), 7.49-7.41 (m, 1H), 7.24-7.12 (m, 5H), 7.00 (d, J=8.4Hz, 2H), 6.94-6.82 (m, 2H), 5.82 (s, 2H), 4.67 (q, J=7.4Hz, 1H), 3.80 (s, 3H), 3.12 (s, 3H), 2.88 (d, J=7.0Hz, 2H)13C NMR(100MHz,DMSO-d6)δ171.26,159.57, 159.08,142.74,137.97,135.93,133.57,133.21,133.01,129.35,129.23,129.05,128.60, 128.31,128.09,127.46,127.19,127.07,126.98,126.88,126.11,115.20,55.91,53.73, 51.73,37.88,37.31.ESI-MS:C31H29N5O3,Exact Mass:519.23,m/z 520.4(M+1)+.
Azide used is 1- azido-methyl naphthalene.Product is white solid, yield: 68%, 78-80 DEG C of fusing point.
1H NMR(400MHz,DMSO-d6) δ 8.54 (s, 1H), 8.33 (d, J=8.0Hz, 1H), 8.16 (d, J=8.1Hz, 1H), 7.99 (t, J=8.5Hz, 2H), 7.57 (ddt, J=20.7,14.9,7.3Hz, 3H), 7.43 (d, J=7.1Hz, 1H), 7.24-7.09 (m, 5H), 6.99 (d, J=8.4Hz, 2H), 6.91-6.80 (m, 2H), 6.15 (s, 2H), 4.64 (q, J= 7.6Hz, 1H), 3.79 (s, 3H), 3.10 (s, 3H), 2.87 (d, J=5.3Hz, 2H)13C NMR(100MHz,DMSO-d6)δ 171.25,159.50,159.06,142.56,137.95,135.91,133.84,131.54,130.99,129.67,129.33, 129.21,128.58,127.85,127.35,127.12,126.88,126.69,126.05,123.59,115.17,55.91, 51.72,51.54,37.86,37.29.ESI-MS:C31H29N5O3,Exact Mass:519.23,m/z 520.4(M+1)+.
Azide used is azido-methyl benzene sulfane.Product is yellow solid, yield: 32%, 64-66 DEG C of fusing point.
1H NMR(400MHz,DMSO-d6) δ 8.43 (s, 1H), 8.38 (d, J=8.0Hz, 1H), 7.42 (d, J=7.3Hz, 2H), 7.34 (q, J=8.2,7.5Hz, 3H), 7.22 (d, J=7.9Hz, 2H), 7.15 (d, J=6.4Hz, 3H), 7.01 (d, J =8.4Hz, 2H), 6.86 (d, J=6.7Hz, 2H), 5.99 (s, 2H), 4.64 (q, J=7.4Hz, 1H), 3.81 (s, 3H), 3.13 (s, 3H), 2.88 (d, J=6.9Hz, 2H)13C NMR(100MHz,DMSO-d6)δ171.25,159.37,159.08, 142.64,138.02,135.93,132.43,131.29,129.83,129.32,129.26,128.59,128.41,126.89, 126.55,115.20,55.93,52.57,51.88,37.89,37.09.ESI-MS:C27H27N5O3S,Exact Mass: 501.18,m/z 502.3(M+1)+.
Azide used is azido-methyl benzene sulfoxide.Product is white solid, yield: 45%, 77-79 DEG C of fusing point.
1H NMR(400MHz,DMSO-d6) δ 8.46 (t, J=9.6Hz, 1H), 8.34 (d, J=25.1Hz, 1H), 7.56 (q, J=6.7,5.8Hz, 5H), 7.37-7.10 (m, 5H), 7.03 (d, J=8.4Hz, 2H), 6.87 (d, J=6.8Hz, 2H), 6.00 (d, J=13.4Hz, 1H), 5.77 (dd, J=13.4,3.6Hz, 1H), 4.66 (q, J=7.4Hz, 1H), 3.82 (s, 3H), 3.14 (s, 3H), 2.90 (d, J=6.8Hz, 2H)13C NMR(100MHz,DMSO-d6)δ171.31,159.26, 159.10,142.07,142.01,140.50,140.42,138.08,135.95,132.17,129.74,129.71,129.32, 128.59,128.28,128.13,126.89,124.89,124.84,115.22,68.55,55.94,51.97,37.91, 37.03.ESI-MS:C27H27N5O4S,Exact Mass:517.18,m/z 518.4(M+1)+.
Azide used is azido-methyl benzene sulfone.Product is light green solid, yield: 56%, 68-70 DEG C of fusing point.
1H NMR(400MHz,DMSO-d6) δ 8.57 (d, J=7.9Hz, 1H), 8.50 (s, 1H), 7.85-7.59 (m, 5H), 7.34-7.12 (m, 5H), 7.09-6.99 (m, 2H), 6.91-6.80 (m, 2H), 6.40 (s, 2H), 4.65 (q, J=7.2Hz, 1H), 3.81 (s, 3H), 3.14 (s, 3H), 2.90 (d, J=6.6Hz, 2H)13C NMR(100MHz,DMSO-d6)δ171.27, 159.11,159.07,142.60,138.06,136.27,135.94,135.47,130.08,129.28,128.99,128.60, 128.50,126.90,115.22,67.46,55.94,52.05,37.90,37.02.ESI-MS:C27H27N5O5S,Exact Mass:533.17,m/z534.3(M+1)+.
External Anti-HIV-1 Active test (MT-4 cell) experiment of 3. target compound of embodiment
Principle: luciferase report gene tests (HIV-1NL4-3 of nef gene delection)
Test method:
Multicycle viral replication assay in MT-4 cell
To being inoculated with MT-4 cell (1x 105Cells/mL in 96 porocyte culture plates), various concentration is added in every hole Target compound (WG1-WG20 and PF-74) then uses HIV-1NL4-3Nanoluc-sec Strain (50TCID50/ hole) infection MT-4 cell.HIV-1NL4-3Nanoluc-sec used is a kind of response virus, it is restricted interior by Not I and Xho I Enzyme cutting site, secNluc sequence in insertion pNL1.3 [secNluc] replace in pNL4-3 plasmid across nucleotide 8796- 8892 Nef sequence.Wherein, Not I site is to import pNL4-3 plasmid by site-directed mutagenesis technique, and Xho I site is Uniqueness site present in pNL4-3 plasmid.After HIV-1NL4-3Nanoluc-sec virus MT-4 is cell 3 days, Supernatant is collected, is passed throughLuciferase report gene detection system (being purchased from Promega) is living to detect its fluorescent Property.Compound activity EC as a result,50It is defined as reducing concentration required when 50% uciferase activity.(Z.Dang, L.Zhu,W.Lai,et al.,Aloperine and Its Derivatives as a New Class of HIV-1Entry Inhibitors,ACS Med Chem Lett.,7(2016)240-244.)
Cell toxicity test
It usesFluorocyte toxotest kit (being purchased from Promega) determines the target chemical combination of synthesis The cytotoxicity of object (WG1-WG20).Presence of the MT-4 cell in the target compound (WG1-WG20 and PF-74) of various concentration Under, continuous culture three days.Then according to the cycle and taking corresponding operation of kit, the cytotoxicity of institute's test target compound is determined (CC50), i.e., target compound reduces cells survival rate by concentration required when 50%.(Z.Dang,L.Zhu,W.Lai,et al.,Aloperine and Its Derivatives as a New Class of HIV-1Entry Inhibitors,ACS Med Chem Lett.,7(2016)240-244.)
Contain phenylalanine derivative HIV-resistant activity, toxicity and selection index (MT-4 cell) of triazole ring in 1. part of table
a EC50: compound concentration of the MT-4 cell of 50% infected by HIV -1 of protection from cytopathy；
bCC50: make 50% cell for being uninfected by HIV-1 that the compound concentration of lesion occur；
cSI: selectivity factor, CC50/EC50Ratio；
: non-selectivity Anti-HIV-1 Active under test concentrations；
PF-74: reported -1 capsid protein inhibitor of a category of HIV, as positive control.
Experiment conclusion analysis: the newly synthesized phenylalanine derivative containing triazole ring shows significant Anti-HIV-1 Active. Compound WG1, WG2, WG3, WG5, WG11, WG12, WG13, WG16, WG19 Anti-HIV-1 Active are in 4.33-14.93 μM of range It is interior, with positive control PF-74 activity (EC50 5.95±1.32μM,CC50> 70.50, SI > 11.85) it is quite or preferable.Wherein change Close the Anti-HIV-1 Active (EC of object WG1650=4.33 ± 0.83 μM, CC50> 57.74, SI > 13.33) it is especially prominent, have into one Walk the value of research.

Claims (7)

1. containing the phenylalanine derivative of triazole ring or its pharmaceutically acceptable salt or ester, which is characterized in that have general formula Structure shown in I:
Wherein,
M=0,1,2,3；
N=0,1,2,3；
R1Are as follows: H, OH, C1-C6Alkyl, OC1-C6Alkyl, C2-C6Alkenyl, C3-C6Naphthenic base, OC3-C6Naphthenic base, trifluoromethyl；
R2Are as follows: H, F, Cl, Br, CF3；
R are as follows: C1-C6Alkyl, OC1-C6Alkyl, C2-C6Alkenyl, C3-C6Naphthenic base, OC3-C6Naphthenic base.
2. the phenylalanine derivative containing triazole ring, which is characterized in that n=0, R1For OCH3,
(1) m=1, R are the substituted benzene ring with a-d general formula；
Wherein, R3For Cl, Me, CN, NO2；X is S, SO, SO2；
(2) m=0, R are Z group, and Z is that Zidovudine removes the group after nitrine, the phenyl or benzo [d] that methoxycarbonyl group replaces [1,3] dioxolyl group.
3. the phenylalanine derivative containing triazole ring, which is characterized in that be one of following compounds:
4. the preparation method of the phenylalanine derivative containing triazole ring as described in claim 1, steps are as follows: with substituted Boc-L- phenylalanine is starting material, intermediate by amide condensed reaction and substituted aniline generation in dichloromethane solution Body B；Then intermediate B is dissolved in q. s. methylene chloride solution, Boc group is sloughed under the action of trifluoroacetic acid, is obtained Mesosome C；Then, intermediate C and propiolic acid, tetrolic acid, pentinoic acid or hexynic acid occur it is amide condensed react to obtain have alkynes piece The key intermediate D of section；Finally, intermediate D and azide pass through Cu under the conditions of sodium ascorbate and cupric sulfate pentahydrate (I) nitrine being catalyzed-alkynes Husigen-Click cycloaddition reaction generates target product I；
Synthetic route is as follows:
Reagent and condition: (i) substituted aniline, 1H- benzotriazole -1- base oxygen tripyrrole alkyl hexafluorophosphate, N, N- diisopropyl Base ethamine, methylene chloride, 0 DEG C, room temperature；(ii) trifluoroacetic acid, methylene chloride, room temperature；(iii) O- (7- azepine benzotriazole -1- Base)-N, N, N', N'- tetramethylurea hexafluorophosphate, n,N-diisopropylethylamine, methylene chloride, 0 DEG C, room temperature；(iv) anti-bad Hematic acid sodium, cupric sulfate pentahydrate, water/tetrahydrofuran, azide, 30-65 DEG C；
Wherein, n, m, R, R1、R2Shown in general formula I with claim 1；
The substituted aniline is N- methyl -4- aminoanisole, N- methyl -4- aminobenzene methanol, N- methyl -4- aminobenzene Phenol；
The azide is substituted benzene ring azide, replaces naphthalene nucleus azide, replace fragrant sulfone, replace aromatic sulfide, take It is generation fragrant sulfoxide, various substituted hexa-member heterocycle azide, various substituted five-ring heterocycles azide, various substituted hexa-atomic And five-ring heterocycles azide, various substituted hexa-atomic and hexa-member heterocycle azide, various substituted five yuan and five-ring heterocycles Azide, various substituted benzo five-membered heterocycle azide or various substituted benzo hexa-member heterocycle azide.
5. the preparation method of the phenylalanine derivative containing triazole ring as claimed in claim 4, steps are as follows:
(1) starting material A is added in dichloromethane solution, 1H- benzo three is then added under condition of ice bath into this solution Azoles -1- base oxygen tripyrrole alkyl hexafluorophosphate stirs 0.5h；Then to being added N in reaction solution, N- diisopropylethylamine and take For aniline, TLC monitoring, to end of reaction, then it is molten that saturated sodium bicarbonate is added in evaporating solvent under reduced pressure into bottle in residue Liquid, ethyl acetate extraction；Divide and take organic layer, 1N HCl solution is added, water phase is extracted with ethyl acetate；Merge organic layer, adds full And brine It, organic phase are dry with anhydrous sodium sulfate；Filtering, evaporated under reduced pressure solvent obtain the crude product of midbody compound B；
(2) the crude Compound B that upper step obtains is added in dichloromethane solution, excessive trifluoro is then added into this solution Acetic acid stirs 8-9h under room temperature；Then the pH=9 that reaction solution is adjusted with saturated sodium bicarbonate solution, adds dichloromethane The extraction of alkane solution；Merging organic layer, saturated common salt water washing 3 times；Anhydrous sodium sulfate is dry；Filtering, evaporated under reduced pressure solvent；Silica gel Pillar layer separation obtains intermediate C sterling；
(3) in the dichloromethane solution for being added to end group acetylenic acid, O- (7- azepine benzotriazole-is then added into this solution 1- yl)-N, N, N', N'- tetramethylurea hexafluorophosphate, ice bath stirring 1h；Intermediate C and N are added into this solution, N- bis- is different After removing ice bath, 7-8h is stirred at room temperature in propylethylamine；Reaction is finished, evaporating solvent under reduced pressure, is then added in residue into bottle full And sodium bicarbonate solution, ethyl acetate extraction；Divide and take organic layer, 1N HCl solution, ethyl acetate extraction is added；Merge organic Layer, adds saturated common salt water washing, and organic phase is dry with anhydrous sodium sulfate；Filtering, evaporated under reduced pressure solvent；Silica gel column chromatography separates To intermediate D sterling；
(4) key intermediate D and azide are added to the in the mixed solvent of tetrahydrofuran and water that volume ratio is 1:1；So Sodium ascorbate, cupric sulfate pentahydrate is added in this backward solution；This mixed solution is heated to 30-65 DEG C and is vigorously stirred 4-12h； Then, suitable water is added into reaction solution, is extracted with ethyl acetate；Divide and take organic layer, anhydrous sodium sulfate is dry；Filtering, subtracts Press solvent evaporated；Silica gel column chromatography separation；Ethyl acetate/petroleum ether or methylene chloride/n-hexane are recrystallized to give triazole type Target compound I.
6. the phenylalanine derivative containing triazole ring treats and prevents AIDS in preparation as described in claim any one of 1-3 Application in drug.
7. a kind of pharmaceutical composition includes the phenylalanine derivative containing triazole ring and one described in claim any one of 1-3 Kind or a variety of pharmaceutically acceptable carriers or excipient.
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CN109796418B (en) * 2019-02-26 2022-03-25 山东大学 Phenylalanine derivative containing 4-phenyl-1, 2, 3-triazole and preparation method and application thereof
CN109897088B (en) * 2019-03-19 2022-06-17 山东大学 Phenylalanine derivative containing N- (2-oxoethyl) benzene sulfonamide and preparation method and application thereof
CN109836477B (en) * 2019-03-19 2022-07-12 山东大学 Phenylalanine derivative containing benzothiadiazine-3-ketone 1, 1-dioxide and preparation method and application thereof
CN109824583B (en) * 2019-03-27 2022-04-08 山东大学 Phenyl oxamide HIV-1 inhibitor and preparation method and application thereof
CN113461636B (en) * 2021-06-04 2023-08-08 山东大学 Benzothiazole-containing phenylalanine derivative and preparation method and application thereof
CN113372335B (en) * 2021-07-05 2023-02-24 山东大学 Phenylalanine derivative containing 1,2, 4-triazole thioether as well as preparation method and application thereof

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