CN108033952A - Phenylalanine derivative containing triazole ring and preparation method and application - Google Patents

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

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CN108033952A
CN108033952A CN201810088488.6A CN201810088488A CN108033952A CN 108033952 A CN108033952 A CN 108033952A CN 201810088488 A CN201810088488 A CN 201810088488A CN 108033952 A CN108033952 A CN 108033952A
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azide
solution
substituted
ring
hexa
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CN108033952B (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 phenylalanine derivative containing triazole ring and preparation method and application.The compound has the structure shown in Formulas I.The invention further relates to the pharmaceutical composition containing Formulas I structural compounds.Composition the present invention also provides above-claimed cpd and containing one or more such compounds is preparing the application in treating and preventing AIDS-treating medicine.

Description

Phenylalanine derivative containing triazole ring and preparation method and application
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 preparation method and application.
Background technology
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 medicine of the treatment AIDS of clinical practice according to action target, is broadly divided into：Reverse 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, the great number of latent infection and prolonged administration of drugs 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 capsids are that assembling is formed after obtaining capsid protein unit by the part shearing of Gag precursor proteins.Not During ripe 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, the HIV-1 virion of maturation is formed.Ripe virus Particle has infectiousness just now, and the next round that can carry out virus replicates.In recent years, as researcher is to capsid protein structure Understand in depth, the relevant information of its crystal structure is also reported successively.Thus, the capsid protein of HIV-1 can resist as new The action target spot of HIV-1.
Pfizer companies obtain significantly inhibiting the compound PF- of HIV-1 duplications 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 disturbs disease by combining HIV-1 capsid proteins The shelling of poison and the process for forming infectious particles.Although PF-74 structures are novel, mechanism is unique, target spot is clear and definite, PF-74 phases The curative effect of medication of anti-HIV-1 for having listed at present is relatively low, 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.
The content 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 preparation Method, the present invention also provides active ingredients result of the above-claimed cpd as HIV-1 capsid protein inhibitor and its application.
Technical scheme is as follows：
1. the phenylalanine derivative containing triazole ring
Phenylalanine derivative containing triazole ring, or its pharmaceutically acceptable salt, ester or prodrug, have general formula I institutes The structure shown：
Wherein,
M=0,1,2,3；
N=0,1,2,3；
R1For：H、OH、C1-C6Alkyl, OC1-C6Alkyl, C2-C6Alkenyl, C3-C6Cycloalkyl, OC3-C6Cycloalkyl, substituted benzene Ring, substituted benzyl, trifluoromethyl, substitution naphthalene nucleus, various substituted hexa-member heterocycles or various substituted five-ring heterocycles；
R2For：H、F、Cl、Br、CF3；
R is：C1-C6Alkyl, OC1-C6Alkyl, C2-C6Alkenyl, C3-C6Cycloalkyl, OC3-C6Cycloalkyl, substituted benzene ring, take For naphthalene nucleus, the fragrant sulfone of substitution, substitution aromatic sulfide, the fragrant sulfoxide of substitution, 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 of kind substitution.
It is preferable according to the present invention,
N=0,
R1For OCH3,
(1) m=1, R are the substituted benzene ring with a-d general formulas；
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 of methoxycarbonyl group substitution, or benzene 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 without unsuitable toxicity, stimulation and allergic reaction etc. with people or compared with the tissue of lower animal, has suitable Rational income and risk ratio, are typically that water or oil are solvable 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 biology obtained by 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, step are as follows：With substituted Boc-L- phenylalanines For starting material, in dichloromethane solution, intermediate B is generated with substituted aniline by amide condensed reaction；Then intermediate B It is dissolved in q. s. methylene chloride solution, Boc groups is sloughed under the action of trifluoroacetic acid, obtains intermediate C；Then, it is middle Body C occurs amide condensed reaction with propiolic acid, tetrolic acid, pentinoic acid or hexynic acid and obtains the key intermediate D with alkynes fragment； Finally, intermediate D passes through nitrine-alkynes of Cu (I) catalysis with azide under the conditions of sodium ascorbate and cupric sulfate pentahydrate Husigen-Click cycloaddition reactions generation target product I.
Synthetic route is as follows：
Reagent and condition：(i) substituted aniline, 1H- benzotriazole -1- base oxygen tripyrrole alkyl hexafluorophosphates, N, N- bis- Wopropyl ethyl amine, dichloromethane, 0 DEG C, room temperature；(ii) trifluoroacetic acid, dichloromethane, room temperature；(iii) O- (7- azepines benzos three Azoles -1- bases)-N, N, N', N'- tetramethylurea hexafluorophosphates, n,N-diisopropylethylamine, dichloromethane, 0 DEG C, room temperature；(iv) Sodium ascorbate, cupric sulfate pentahydrate, water/tetrahydrofuran, azide, 30-65 DEG C.
Wherein, n, m, R, R1、R2Shown in above-mentioned general formula I.
The substituted aniline is N- methyl -4- aminoanisoles, N- methyl -4- aminobenzenes methanol, N- methyl -4- amino Phenol.
The azide is substituted benzene ring azide, substitution naphthalene nucleus azide, the fragrant sulfone of substitution, the fragrant sulphur of substitution Ether, the fragrant sulfoxide of substitution, 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 heterocycles azide, various substituted benzo five-membered heterocycle azide or various substituted benzo hexa-member heterocycle Azides Thing.
Room temperature of the present invention is 20-30 DEG C.
Preferable according to the present invention, the preparation method of the phenylalanine derivative containing triazole ring, comprises the following steps that：
(1) starting material A is added in dichloromethane solution, then adds 1H- benzene under condition of ice bath into this solution And triazol-1-yl oxygen tripyrrole alkyl hexafluorophosphate, stir 0.5h；Then to adding N, N- diisopropylethylamine in reaction solution And substituted aniline, TLC monitorings, question response finish, remove solvent under reduced pressure, then add saturated sodium bicarbonate in residue into bottle Solution, ethyl acetate extraction；Divide and take organic layer, add 1N HCl solutions, water is mutually extracted with ethyl acetate；Merge organic layer, add Saturated common salt water washing, organic phase are dried 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 of reaction solution is adjusted with saturated sodium bicarbonate solution, adds two Chloromethanes solution extracts；Merge organic layer, saturated common salt water washing 3 times；Anhydrous sodium sulfate is dried；Filtering, evaporated under reduced pressure solvent； The isolated intermediate C sterlings of silica gel column chromatography；
(3) in the dichloromethane solution for being added to end group acetylenic acid, O- (7- azepines benzos three are then added into this solution Azoles -1- bases)-N, N, N', N'- tetramethylurea hexafluorophosphates, ice bath stirring 1h；Intermediate C and N, N- are added into this solution Diisopropylethylamine, after removing ice bath, is stirred at room temperature 7-8h；Reaction is finished, and removes solvent under reduced pressure, is then added into bottle in residue Enter saturated sodium bicarbonate solution, ethyl acetate extraction；Divide and take organic layer, add 1N HCl solutions, ethyl acetate extraction；It is associated with Machine layer, adds saturated common salt water washing, and organic phase is dried with anhydrous sodium sulfate；Filtering, evaporated under reduced pressure solvent；Silica gel column chromatography separates Obtain intermediate D sterlings；
(4) key intermediate D and azide are added to volume ratio as 1:1 tetrahydrofuran and the mixed solvent of water 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 drying；Cross Filter, evaporated under reduced pressure solvent；Silica gel column chromatography separates；Ethyl acetate/petroleum ether or dichloromethane/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 The first Application of inhibitor.Being experimentally confirmed the phenylalanine derivative containing triazole ring of the present invention can be used as HIV-1 to suppress Agent is used to prepare anti-AIDS drug.The present invention also provides the application in above-claimed cpd 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, and are suppressed with existing capsid protein Agent PF-74 is positive control.
The phenylalanine derivative containing triazole ring that the present invention newly synthesizes shows significant Anti-HIV-1 Active.For example, change Compound WG1, WG2, WG3, WG5, WG11, WG12, WG13, WG16, WG19 Anti-HIV-1 Active in the range of 4.33-14.93 μM, With positive control PF-74 activity (EC50=5.95 ± 1.32 μM, CC50>70.50,SI>11.85) it is more excellent or suitable, wherein chemical combination Anti-HIV-1 Active (the EC of thing 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 present invention can be used as HIV-1 inhibitor applications.Specifically, Anti-AIDS drug is used to prepare as HIV-1 inhibitor.
A kind of anti-HIV-1 medicines composition, includes a kind of phenylalanine derivative containing triazole ring and one of the present invention Kind or a variety of pharmaceutically acceptable carriers or excipient.
The present invention provides the phenylalanine derivative of one kind containing triazole ring and preparation method thereof, present invention also offers Part of compounds Anti-HIV-1 Active the selection result and its first Application in antiviral field.Test proves that the present invention A kind of phenylalanine derivative containing triazole ring can be applied as HIV-1 inhibitor and there is very high application value.Tool Say body, anti-AIDS drug is used to prepare as HIV-1 inhibitor.
Embodiment
Contribute to understand the present invention by following embodiments, but present disclosure cannot be limited.
Involved synthetic route is as follows in embodiment：
Embodiment 1：Key intermediate (S)-N- (1- (4- methoxyphenyls) (methyl) amino) -1- carbonyl -3- phenyl -2- Base) propine acid amides (4) preparation
The anhydrous methylene chloride that starting material Boc-L- phenylalanines (1) (8.75mmol, 2.3g) are added to 15mL is molten In liquid, 1H- benzotriazole -1- base oxygen tripyrrole alkyl hexafluorophosphates (10.9mmol, 5.7g) are then added into this solution. 0.5h is stirred under condition of ice bath, then adds n,N-diisopropylethylamine (21.87mmol, 3.61mL) and N- methyl -4- amino Methyl phenyl ethers anisole (7.29mmol, 1.0g), removes ice bath, 12h is stirred at room temperature.Question response finishes, and solvent is removed under reduced pressure, then into bottle Saturated sodium bicarbonate solution, ethyl acetate extraction are added in residue；Divide and take organic layer, add 1N HCl solutions, ethyl acetate Extraction；Merge organic layer, add saturated common salt water washing, organic phase is dried with anhydrous sodium sulfate；Filtering, evaporated under reduced pressure solvent obtain The midbody compound tert-butyl group-(S)-(1- ((4- methoxyphenyls) (methyl) amino) -1- oxo -3- phenylpropyl -2- bases) 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 dichloromethane, then to this Trifluoroacetic acid (34.2mmol, 5.0eq) is added in solution, 8-9h is stirred at room temperature.Then adjusted with saturated sodium bicarbonate solution anti- The pH=9 of liquid is answered, adds dichloromethane solution extraction；Merge organic layer, saturated common salt water washing 3 times；Anhydrous sodium sulfate is dried； Filter, be concentrated under reduced pressure, the isolated intermediate of silica gel column chromatography (S) -2- amino-N- (4- methoxyphenyls)-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 benzos triazol-1-yl)-N, N into this solution, N', N'- tetramethylureas hexafluorophosphate (5.28mmol, 2.0g), stir 1h under condition of ice bath, then in this solution add n,N-diisopropylethylamine (7.03mmol, 1.16mL) and Intermediate 3, removes ice bath, stirs 7-8h under room temperature；Question response finishes, and removes solvent under reduced pressure, then the residue into bottle Middle addition saturated sodium bicarbonate solution, ethyl acetate extraction；Divide and take organic layer, add 1N HCl solutions, ethyl acetate extraction；Close And organic layer, add saturated common salt water washing, organic phase is dried with anhydrous sodium sulfate；Filtering, evaporated under reduced pressure solvent；Silica gel column chromatography Isolated intermediate (S)-N- (1- (4- methoxyphenyls) (methyl) amino) -1- carbonyl -3- phenyl -2- bases) propine acid amides (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
Key intermediate 4 (0.297mmol, 1eq) and the azide (0.357mmol, 1.2eq) prepared are added to four Mixed solvent (the v/v=1 of hydrogen furans and water:In 1,10mL).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 take organic layer, anhydrous slufuric acid Sodium is dried；Filtering, evaporated under reduced pressure solvent；Silica gel column chromatography separates；Ethyl acetate/petroleum ether or dichloromethane/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- chlorobenzenes.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- chlorobenzenes.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- chlorobenzenes.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- nitrobenzenes.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- nitrobenzenes.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- nitrobenzenes.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 naphthalenes.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 naphthalenes.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 cells) experiment of 3. target compound of embodiment
Principle：Luciferase report gene tests (HIV-1NL4-3 of nef gene delections)
Test method：
Multicycle viral replication assay in MT-4 cells
To being inoculated with MT-4 cells (1x 105Cells/mL in 96 porocyte culture plates), various concentrations are added per hole Target compound (WG1-WG20 and PF-74), then uses HIV-1NL4-3Nanoluc-sec Strain (50TCID50/ hole) infection MT-4 cells.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 sequences in insertion pNL1.3 [secNluc] replace crossing over nucleotide 8796- in pNL4-3 plasmids 8892 Nef sequences.Wherein, Not I sites are to import pNL4-3 plasmids by site-directed mutagenesis technique, and Xho I sites are Unique site present in pNL4-3 plasmids.After HIV-1NL4-3Nanoluc-sec virus MT-4 cells 3 days, Collect supernatant, pass throughLuciferase report gene detecting system (being purchased from Promega) is lived to detect its fluorescent Property.Thus, compound activity EC50It is defined as reducing concentration required during 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
UseFluorocyte toxotest kit (being purchased from Promega) determines the target chemical combination of synthesis The cytotoxicity of thing (WG1-WG20).Presence of the MT-4 cells in the target compound (WG1-WG20 and PF-74) of various concentrations 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 makes cells survival rate reduce 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 the selection index (MT-4 cells) of triazole ring in 1. part of table
a EC50:Protect the MT-4 cells of 50% infected by HIV -1 from the compound concentration of 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:The capsid protein inhibitor of a category of HIV -1 reported, as positive control.
Experiment conclusion is analyzed：The phenylalanine derivative containing triazole ring newly synthesized 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 scope 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 Anti-HIV-1 Active (the EC of compound 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. the phenylalanine derivative containing triazole ring, or its pharmaceutically acceptable salt, ester or prodrug, it is characterised in that tool There is the structure shown in general formula I：
Wherein,
M=0,1,2,3；
N=0,1,2,3；
R1For：H、OH、C1-C6Alkyl, OC1-C6Alkyl, C2-C6Alkenyl, C3-C6Cycloalkyl, OC3-C6Cycloalkyl, substituted benzene ring, take For benzyl, trifluoromethyl, substitution naphthalene nucleus, various substituted hexa-member heterocycles or various substituted five-ring heterocycles；
R2For：H、F、Cl、Br、CF3；
R is：C1-C6Alkyl, OC1-C6Alkyl, C2-C6Alkenyl, C3-C6Cycloalkyl, OC3-C6Cycloalkyl, substituted benzene ring, substitution naphthalene It is ring, the fragrant sulfone of substitution, substitution aromatic sulfide, the fragrant sulfoxide of substitution, various substituted hexa-member heterocycles, various substituted five-ring heterocycles, various The hexa-atomic and five-ring heterocycles of substitution, various substituted hexa-atomic and hexa-member heterocycles, various substituted five yuan and five-ring heterocycles, various take The benzo five-membered heterocycle in generation or various substituted benzo hexa-member heterocycles.
2. the phenylalanine derivative containing triazole ring as claimed in claim 1, it is characterised in that n=0, R1For OCH3,
(1) m=1, R are the substituted benzene ring with a-d general formulas；
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 of methoxycarbonyl group substitution, or benzo [d] [1,3] dioxolyl group.
3. the phenylalanine derivative containing triazole ring as claimed in claim 1, it is characterised in that be following compounds it One：
4. the preparation method of the phenylalanine derivative containing triazole ring, step are as follows as claimed in claim 1：With substituted Boc-L- phenylalanines are starting material, middle 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 groups is sloughed under the action of trifluoroacetic acid, in obtaining Mesosome C；Then, intermediate C obtains carrying alkynes piece with the amide condensed reaction of propiolic acid, tetrolic acid, pentinoic acid or hexynic acid generation The key intermediate D of section；Finally, intermediate D passes through Cu with azide under the conditions of sodium ascorbate and cupric sulfate pentahydrate (I) nitrine of catalysis-alkynes Husigen-Click cycloaddition reactions generation target product I；
Synthetic route is as follows：
Reagent and condition：(i) substituted aniline, 1H- benzotriazole -1- base oxygen tripyrrole alkyl hexafluorophosphates, N, N- diisopropyls Base ethamine, dichloromethane, 0 DEG C, room temperature；(ii) trifluoroacetic acid, dichloromethane, room temperature；(iii) O- (7- azepine benzotriazole -1- Base)-N, N, N', N'- tetramethylurea hexafluorophosphates, n,N-diisopropylethylamine, dichloromethane, 0 DEG C, room temperature；(iv) it is anti-bad Hematic acid sodium, cupric sulfate pentahydrate, water/tetrahydrofuran, azide, 30-65 DEG C；
Wherein, n, m, R, R1、R2Shown in the general formula I of claim 1；
The substituted aniline is N- methyl -4- aminoanisoles, N- methyl -4- aminobenzenes methanol, N- methyl -4- aminobenzenes Phenol；
The azide is substituted benzene ring azide, substitutes the fragrant sulfone of naphthalene nucleus azide, substitution, substitution aromatic sulfide, takes 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, step are as follows as claimed in claim 4：
(1) starting material A is added in dichloromethane solution, then adds 1H- benzos three under condition of ice bath into this solution Azoles -1- base oxygen tripyrrole alkyl hexafluorophosphates, stir 0.5h；Then to adding N in reaction solution, N- diisopropylethylamine and take For aniline, TLC monitorings, question response finishes, and removes solvent under reduced pressure, and it is molten then to add saturated sodium bicarbonate in residue into bottle Liquid, ethyl acetate extraction；Divide and take organic layer, add 1N HCl solutions, water is mutually extracted with ethyl acetate；Merge organic layer, add full And brine It, organic phase are dried 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 of reaction solution is adjusted with saturated sodium bicarbonate solution, adds dichloromethane Alkane solution extracts；Merge organic layer, saturated common salt water washing 3 times；Anhydrous sodium sulfate is dried；Filtering, evaporated under reduced pressure solvent；Silica gel Pillar layer separation obtains intermediate C sterlings；
(3) in the dichloromethane solution for being added to end group acetylenic acid, then into this solution add O- (7- azepines benzotriazole- 1- yls)-N, N, N', N'- tetramethylurea hexafluorophosphates, ice bath stirring 1h；It is different that intermediate C and N, N- bis- is added into this solution Propylethylamine, after removing ice bath, is stirred at room temperature 7-8h；Reaction is finished, and removes solvent under reduced pressure, is then added into bottle in residue full And sodium bicarbonate solution, ethyl acetate extraction；Divide and take organic layer, add 1N HCl solutions, ethyl acetate extraction；Merge organic Layer, adds saturated common salt water washing, organic phase is dried with anhydrous sodium sulfate；Filtering, evaporated under reduced pressure solvent；Silica gel column chromatography separates To intermediate D sterlings；
(4) key intermediate D and azide are added to volume ratio as 1:1 tetrahydrofuran and the in the mixed solvent of water；So Sodium ascorbate, cupric sulfate pentahydrate are 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 drying；Filtering, subtracts Press solvent evaporated；Silica gel column chromatography separates；Ethyl acetate/petroleum ether or dichloromethane/n-hexane are recrystallized to give triazole type Target compound I.
6. the phenylalanine derivative containing triazole ring is preparing treatment and prevention AIDS as described in claim any one of 1-3 Application in medicine.
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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CN109796418A (en) * 2019-02-26 2019-05-24 山东大学 Phenylalanine derivative and the preparation method and application thereof containing 4- phenyl -1,2,3- triazole
CN109824583A (en) * 2019-03-27 2019-05-31 山东大学 A kind of phenyl Oxamides HIV-1 inhibitor and its preparation method and application
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CN113372335A (en) * 2021-07-05 2021-09-10 山东大学 Phenylalanine derivative containing 1,2, 4-triazole thioether and preparation method and application thereof
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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
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CN109897088A (en) * 2019-03-19 2019-06-18 山东大学 Phenylalanine derivative and the preparation method and application thereof containing N- (2- oxoethyl) benzsulfamide
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
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CN109824583A (en) * 2019-03-27 2019-05-31 山东大学 A kind of phenyl Oxamides HIV-1 inhibitor and its preparation method and application
CN109824583B (en) * 2019-03-27 2022-04-08 山东大学 Phenyl oxamide HIV-1 inhibitor and preparation method and application thereof
CN113461636A (en) * 2021-06-04 2021-10-01 山东大学 Benzothiazole-containing phenylalanine derivative and preparation method and application thereof
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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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