CN102558157A - Ethoxyl-triazole compound or amonoethyl-triazole compound and preparation method and application thereof - Google Patents

Ethoxyl-triazole compound or amonoethyl-triazole compound and preparation method and application thereof Download PDF

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CN102558157A
CN102558157A CN2010105999305A CN201010599930A CN102558157A CN 102558157 A CN102558157 A CN 102558157A CN 2010105999305 A CN2010105999305 A CN 2010105999305A CN 201010599930 A CN201010599930 A CN 201010599930A CN 102558157 A CN102558157 A CN 102558157A
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straight
branched alkyl
amino
methyl
heteroaryl
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CN102558157B (en
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沈竞康
李佳
朱义平
许磊
马兰萍
章海燕
王昕�
付燕
邹贻泉
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Shanghai Institute of Materia Medica of CAS
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    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
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Abstract

The invention discloses an ethoxyl-triazole compound or an amonoethyl-triazole compound with the following constitutional formula and the preparation method and the application thereof. A bioactivity test proves that the compound has obvious activity to restrain beta-secretase. Therefore, the ethoxyl-triazole compound or the amonoethyl-triazole compound can be an inhibitor of the beta-secretase to prevent or treat Alzheimer disease.

Description

Hydroxyethyl triazole class compounds or aminoethyl triazole class compounds
Technical field
The present invention relates to hydroxyethyl triazole class compounds or aminoethyl triazole class compounds.
Background technology
Presenile dementia (Alzheimer ' s disease, hereinafter referred AD) is a kind of chronic nerve degenerative diseases that is common in elderly population, and its clinical manifestation is that carrying out the property disturbance of intelligence, hypomnesis, the mental act that increase the weight of are unusual etc.The elderly's health in its serious threat, especially current society aging gradually, and this situation is all the more severe, has caused people's common concern.
Acetylcholinesterase depressant remains the main medicine of clinical treatment AD at present; Though can reverse study, memory impairment that the choline function damage causes; The part patient symptom is alleviated, but can not fundamentally change morbid state (Barril, X.et al Mini Rev.Med.Chem.2001; 1,255).
Research in recent years shows that the generation of the amyloid beta in the brain (β-amyloid peptide, hereinafter referred A β) and gathering are considered to cause an important factor of this disease generation.A β is the polypeptide of about 4kD of being produced by amyloid precursor protein (amyloidprecursor protein, hereinafter referred APP) hydrolysis, and what its terminal 11-15 amino acid was positioned at APP strides the film district.Mainly contain three kinds of Secretasess and participated in hydrolytic process, be called α, β and gamma-secretase respectively APP.The restriction enzyme site of alpha-secretase enzyme is positioned at A β sequence, acts on and produces soluble α-APP fragment and C83 peptide behind the APP, and the C83 peptide can continue the peptide by gamma-secretase hydrolysis generation P3, does not produce A β.And the restriction enzyme site of beta-secretase is positioned at first amino acid of A β N end, produces β-APP and C99 peptide after acting on APP, and the C99 peptide is again through gamma-secretase effect generation A β.This shows that beta-secretase is a rate-limiting enzyme very crucial in the A β forming process.And the mouse demonstration that knocks out the beta-secretase gene does not have the generation of A β not have the obstacle of tangible nerve and other physiological function aspect simultaneously fully; Therefore beta-secretase is considered to treat the safe and effective novel targets of AD (D.J.Selkoe Science.2002; 297,353-356.).And the suppressor factor of beta-secretase is more safer than gamma-secretase inhibitors, but the synthetic difficulty of micromolecular beta-secretase inhibitors is far above inhibitors of gamma-secretase.
Summary of the invention
For solving the technical problem that exists in the prior art, the inventor has designed and synthesized a series of beta-secretase inhibitors, in the hope of reaching the purpose of treatment AD.
Therefore, an object of the present invention is to provide and a kind of beta-secretase is had inhibiting hydroxyethyl triazole class compounds or aminoethyl triazole class compounds or its pharmacy acceptable salt.
Another object of the present invention provides the preparation method of this compounds.
A purpose more of the present invention provides the purposes of this compounds as beta-secretase inhibitor, and promptly it is as the medicinal application of treatment AD.
For realizing above-mentioned purpose, the invention provides hydroxyethyl triazole class compounds or aminoethyl triazole class compounds or its pharmacy acceptable salt represented like following general formula I:
Figure BSA00000394448800021
Wherein:
R 1For
Figure BSA00000394448800022
Figure BSA00000394448800023
Figure BSA00000394448800024
Wherein, X is NH, O or CH 2Y does
Figure BSA00000394448800025
Or CH 2R 6Be H, C 1-C 6Straight or branched alkyl or C 3-C 6Naphthenic base;
R 2For
Figure BSA00000394448800026
H, C 1-C 4Straight or branched alkyl, nitro, cyanic acid, ethanoyl or halogen; Wherein, R 7Be H, C 1-C 6Straight or branched alkyl or C 3-C 6Naphthenic base; R 8Be H, C 1-C 6Straight or branched alkyl or C 3-C 6Naphthenic base;
R 3Be C 1-C 6Straight or branched alkyl, phenyl or heteroaryl;
W and V are identical or different, are CH or N independently of one another;
Z is OH or NH 2
R 4And R 5Identical or different, be H, C independently of one another 1-C 6Straight or branched alkyl, phenyl, heteroaryl, C 3-C 6Naphthenic base, C 3-C 6Methyl cycloalkyl, C 1-C 6Carboxyl ester group, ethanoyl, N, N-dimethylaminomethyl, C 1-C 6Carboxamido-group, hydroxyl, amino, cyanic acid, trifluoromethyl, halogen,
Figure BSA00000394448800031
Wherein n is the integer of 1-3, R 9Be H, ethanoyl, C 1-C 6Straight or branched alkyl, C 3-C 6Naphthenic base, C 6-C 10Aryl, heteroaryl, benzyl or α-acrinyl, R 10Be C 1-C 6Straight or branched alkyl, C 3-C 6Naphthenic base, the substituted Phenoxymethyl of trifluoromethyl, C 6-C 10Aryl or heteroaryl;
Wherein, said phenyl is not necessarily by C 1-C 6Straight or branched alkyl, halogen, trifluoromethyl, methoxyl group, amino or cyanic acid replace, said C 6-C 10Aryl is not necessarily by C 1-C 6Straight or branched alkyl, halogen, trifluoromethyl, methoxyl group, amino or cyanic acid replace, and said heteroaryl is to contain 1-3 heteroatomic five yuan or the six membered heteroaryl that is selected among N, S and the O.
In the present invention's one embodiment preferred, Z is OH in the above-mentioned general structure, and promptly said compound is the hydroxyethyl triazole class compounds;
And further preferred:
W and V are respectively CH;
R 1For
Figure BSA00000394448800032
Wherein, X is NH; Y does
Figure BSA00000394448800033
R 6Be H or C 1-C 6The straight or branched alkyl;
R 2For Nitro or H; Wherein, R 7Be H, C 1-C 6Straight or branched alkyl or C 3-C 6Naphthenic base; R 8Be H, C 1-C 6Straight or branched alkyl or C 3-C 6Naphthenic base;
R 3Be phenyl;
R 4And R 5Identical or different, be H, C independently of one another 1-C 6Straight or branched alkyl, phenyl, heteroaryl, C 3-C 6Naphthenic base, C 3-C 6Methyl cycloalkyl, C 1-C 6Carboxyl ester group, ethanoyl, N, N-dimethylaminomethyl, C 1-C 6Carboxamido-group, hydroxyl, amino, cyanic acid, trifluoromethyl, halogen,
Figure BSA00000394448800035
Wherein n is the integer of 1-3, R 9Be H, ethanoyl, C 1-C 6Straight or branched alkyl, C 3-C 6Naphthenic base, C 6-C 10Aryl, heteroaryl, benzyl or α-acrinyl, R 10Be C 1-C 6Straight or branched alkyl, C 3-C 6Naphthenic base, F 3The substituted Phenoxymethyl of C, C 6-C 10Aryl or heteroaryl;
Wherein, said phenyl is not necessarily by C 1-C 6Straight or branched alkyl, halogen, trifluoromethyl, methoxyl group, amino or cyanic acid replace, said C 6-C 10Aryl is not necessarily by C 1-C 6Straight or branched alkyl, halogen, trifluoromethyl, methoxyl group, amino or cyanic acid replace, and said heteroaryl is to contain 1-3 heteroatomic five yuan or the six membered heteroaryl that is selected among N, S and the O.
In another embodiment preferred of the present invention, said R 4And R 5Identical or different, be H, C independently of one another 1-C 6Straight or branched alkyl, phenyl, heteroaryl, C 3-C 6Naphthenic base, C 3-C 6Methyl cycloalkyl, C 1-C 6Carboxyl ester group, ethanoyl, N, N-dimethylaminomethyl, C 1-C 6Carboxamido-group, hydroxyl, amino, cyanic acid, trifluoromethyl, halogen,
Figure BSA00000394448800041
Figure BSA00000394448800042
Wherein n is the integer of 1-3, R 9Be H, ethanoyl, C 1-C 6Straight or branched alkyl, C 3-C 6Naphthenic base, phenyl, benzyl or α-acrinyl, R 10Be C 1-C 6Straight or branched alkyl, C 3-C 6Naphthenic base, phenyl or F 3The substituted Phenoxymethyl of C; Wherein, said phenyl is not necessarily by C 1-C 6Straight or branched alkyl, halogen, trifluoromethyl, methoxyl group, amino or cyanic acid replace, and said heteroaryl is to contain 1-3 heteroatomic five yuan or the six membered heteroaryl that is selected among N, S and the O.
According to another object of the present invention, the invention provides the preparation method of hydroxyethyl triazole class compounds, this method is used following synthetic route 1,2 or 3:
Synthetic route 1:
Figure BSA00000394448800051
Reactions step is following:
A) be starting raw material with epoxy compounds A, with sodiumazide in the presence of ammonium chloride be that solvent refluxing reaction open loop gets compd B with methyl alcohol,
B) B preferably sloughs the basic Compound C that gets of Boc protection under the condition of trifluoroacetic acid or hydrochloric acid under acidic conditions,
C) at EDCI (1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride), HOBt (1-hydroxy benzo triazole) and DIPEA (N; The N-diisopropylethylamine) under the condition that one or more compounds exist in; Compound C further gets Compound D with R1 and the substituted phenylformic acid condensation of R2
D) the synthetic of the substituted hydroxyethyl triazole class compounds in 4-position E is with copper salt catalyst, and anti-sepsis acid sodium is reductive agent, makes Compound D at THF (THF)/H 2In down reaction 24-48 hour of 50 ℃ of reactions, obtain in the O mixed solvent through silicagel column or thin plate layer analysis method, wherein, preferred cupric sulfate pentahydrate of said mantoquita or cuprous iodide.
Synthetic route 2:
Figure BSA00000394448800052
Wherein, reactions step a), b), c) the same, reactions step d) in:
It is with Ru (PPh that the 5-position replaces the synthetic of hydroxyethyl triazole class compounds F 3) 2Cl 2Being catalyzer, is solvent with THF, make Compound D the heating condition under with
Figure BSA00000394448800061
Reacted 12-24 hour, and obtained through silicagel column or thin plate layer analysis method;
Perhaps, synthetic route 3:
Wherein, reactions step a), b), c) the same, reactions step d) in:
4; The synthetic of the dibasic hydroxyethyl triazole class compounds of 5-G is alternatively by copper catalysis; It directly is solvent with toluene; Reaction obtains with under the condition of heating to make Compound D; Wherein, iodine substituted two substitution compounds in 5-position then obtain under copper catalysis.
Again in the embodiment preferred, Z is NH in the above-mentioned general structure in the present invention 2, promptly said compound is the aminoethyl triazole class compounds;
And further preferred:
W and V are respectively CH;
R 1For
Figure BSA00000394448800064
Wherein, X is NH; Y does
Figure BSA00000394448800065
R 6Be H or C 1-C 6The straight or branched alkyl;
R 2For
Figure BSA00000394448800066
Nitro or H; Wherein, R 7Be H, C 1-C 6Straight or branched alkyl or C 3-C 6Naphthenic base; R 8Be H, C 1-C 6Straight or branched alkyl or C 3-C 6Naphthenic base;
R 3Be phenyl;
R 4And R 5Identical or different, be H, C independently of one another 1-C 6Straight or branched alkyl, phenyl, heteroaryl, C 3-C 6Naphthenic base, C 3-C 6Methyl cycloalkyl, C 1-C 6Carboxyl ester group, ethanoyl, N, N-dimethylaminomethyl, C 1-C 6Carboxamido-group, hydroxyl, amino, cyanic acid, trifluoromethyl, halogen,
Figure BSA00000394448800071
Wherein n is the integer of 1-3, R 9Be H, ethanoyl, C 1-C 6Straight or branched alkyl, C 3-C 6Naphthenic base, C 6-C 10Aryl, heteroaryl, benzyl or α-acrinyl, R 10Be C 1-C 6Straight or branched alkyl, C 3-C 6Naphthenic base, F 3The substituted Phenoxymethyl of C, C 6-C 10Aryl or heteroaryl;
Wherein, said phenyl is not necessarily by C 1-C 6Straight or branched alkyl, halogen, trifluoromethyl, methoxyl group, amino or cyanic acid replace, said C 6-C 10Aryl is not necessarily by C 1-C 6Straight or branched alkyl, halogen, trifluoromethyl, methoxyl group, amino or cyanic acid replace, and said heteroaryl is to contain 1-3 heteroatomic five yuan or the six membered heteroaryl that is selected among N, S and the O.
In the another embodiment preferred of the present invention, said R 4And R 5Identical or different, be H, C independently of one another 1-C 6Straight or branched alkyl, phenyl, heteroaryl, C 3-C 6Naphthenic base, C 3-C 6Methyl cycloalkyl, C 1-C 6Carboxyl ester group, ethanoyl, N, N-dimethylaminomethyl, C 1-C 6Carboxamido-group, hydroxyl, amino, cyanic acid, trifluoromethyl, halogen,
Figure BSA00000394448800072
Figure BSA00000394448800073
Wherein n is the integer of 1-3, R 9Be H, ethanoyl, C 1-C 6Straight or branched alkyl, C 3-C 6Naphthenic base, phenyl, benzyl or α-acrinyl, R 10Be C 1-C 6Straight or branched alkyl, C 3-C 6Naphthenic base, phenyl or F 3The substituted Phenoxymethyl of C; Wherein, said phenyl is not necessarily by C 1-C 6Straight or branched alkyl, halogen, trifluoromethyl, methoxyl group, amino or cyanic acid replace, and said heteroaryl is to contain 1-3 heteroatomic five yuan or the six membered heteroaryl that is selected among N, S and the O.
According to another object of the present invention, the invention provides the preparation method of aminoethyl triazole class compounds, this compounds can be synthetic through following route:
Figure BSA00000394448800081
Reactions step is following:
A) be starting raw material with epoxy compounds H, with phthalic diamide at triphenyl phosphorus, it is that solvent gets compound I in the room temperature reaction open loop with THF down that the azoformic acid isopropyl ester exists,
B) compound I is preferably sloughed the basic compound J of getting of Boc protection under the condition of trifluoroacetic acid or hydrochloric acid under acidic conditions,
C) compound J further gets compound K with R1 and the condensation in the presence of EDCI, HOBt, DIPEA of the substituted phenylformic acid of R2,
D) the synthetic of 4-position replacement aminoethyl triazole class compounds L is to be catalyzer with the mantoquita, and anti-sepsis acid sodium is reductive agent, makes compound K at THF/H 2In down reaction 24-48 hour of 50 ℃ of reactions, obtain in the mixed solvent of O through silicagel column or thin plate layer analysis method, wherein, the preferred cupric sulfate pentahydrate of said mantoquita.
According to hydroxyethyl triazole class compounds provided by the present invention or aminoethyl triazole class compounds or its pharmacy acceptable salt, be preferably one of following compound:
Figure BSA00000394448800091
Figure BSA00000394448800101
Figure BSA00000394448800111
Figure BSA00000394448800121
Figure BSA00000394448800131
Figure BSA00000394448800141
According to a purpose more of the present invention, the invention provides this compounds as beta-secretase inhibitor, be used to prevent, delay or treat the purposes in the disease, particularly AD medicine that the deposition by A β causes in preparation.
Hydroxyethyl triazole class compounds of the present invention or aminoethyl triazole class compounds; Activity with obvious suppression beta-secretase; This possibly have the cognitive function of improvement for further research, and the original new drug of alleviating the AD PD simultaneously provides valuable information.
Embodiment
Below in conjunction with embodiment the present invention is done further elaboration, following embodiment is only described the present invention by way of example.Clearly, those of ordinary skills can carry out various accommodations and modification to the present invention in scope of the present invention and essence.Need be appreciated that, this invention is intended to be encompassed in the flexible and modification that comprises in the appended claims.
Experiment and the used instrument of sample analysis:
Nuclear magnetic resonance spectrum (1H NMR) is by the Mercury-300 or the Mercury-400 type nmr determination of Varian company.
LC-MS is measured by Thermo Finnigan LCQDECA * P type mass spectrograph.
HRMS is measured by Finnigan MAT 95 type mass spectrographs.
Sample purity is measured by the high performance liquid chromatograph (306pump, uv/vis-156 Detector, 215 liquidhandle) of Gilson company.
The optically-active data are measured by PerkinElmer-341 type polarimeter.
The column chromatography for separation used silica gel is Haiyang Chemical Plant, Qingdao's product (a 200-300 order).
The TLC silica-gel plate is the HSF-254 thin-layer chromatography precoated plate of Yantai Chemical Manufacture.
Uv lamp is the Shanghai ZF-1 of a Gu Cun electric light instrument plant type ultraviolet analysis instrument for three purposed.
Microwave reactor is a Biotage Initiator product.
Preparation embodiment (the embodiments of the invention numbering is with the compound numbering)
Embodiment 1:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-phenyl-1,2,3-triazoles base)-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic route:
Figure BSA00000394448800151
Reactions step:
(2S, 3S)-1, (the N-tertiary butyloxycarbonyl is amino)-(770mg 2.93mmol) is dissolved in the 20mL methyl alcohol 4-phenylpropyl alcohol alkane 2-epoxy-3-, in system, adds NH with epoxy compounds 4Cl (282mg, 5.27mmol), NaN 3(457mg, 7.03mmol).Be heated to reflux state, reaction is spent the night to no raw material residue.Reaction solution is concentrated, in system, add 30mL water, ethyl acetate extraction 2 times, each 30mL (30mL * 2); Merge organic phase, Diluted Acid Washing (15mL * 2), saturated sodium bicarbonate is washed (15mL * 2), saturated common salt washing (20mL); Anhydrous sodium sulfate drying filters, and concentrates, and gets white solid (2S; 3S)-and 1-benzyl-2-hydroxyl-3-azido-t-butyl carbamate 810mg, yield: 90.3%, fusing point: 99-101 ℃.
1H?NMR(300MHz，CDCl 3)：δ7.25(m，5H)，4.60(d，J＝8.4Hz，1H)，3.80(m，2H)，3.40(m，3H)，2.92(m，2H)，1.37(s，9H)；
LC-MS：m/z?306.7[M+H] +；
[α] D 19＝-51.5°(c?1.000，MeOH)。
(92mg 0.3mmol) is dissolved in the 4mL methylene dichloride, in system, adds 1mL trifluoroacetic acid, room temperature reaction 3h with above-mentioned trinitride.Concentrate not treated next step reaction of direct entering of the amine that obtains.With 5-(methyl methylsulfonyl) amino-3-((1R)-1-(4-fluorophenyl)) ethyl aminocarbonyl phenylformic acid (106mg 0.27mmol) is dissolved among the 2mL DMF, add EDCI (52mg, 0.27mmol), HOBt (37mg, 0.27mmol), stirring at room 10min.The amine that the last step was obtained is dissolved in the DMF of 2mL, and (99 μ l 0.6mmol), splash into above-mentioned reaction system with it, then the following 70 ℃ of reaction 15min of microwave condition to add DIPEA.In system, add 30mL water, ethyl acetate extraction (30mL * 2) merges organic phase; Diluted Acid Washing (15mL * 2), saturated sodium bicarbonate is washed (15mL * 2), saturated common salt washing (20mL); Anhydrous sodium sulfate drying filters, and concentrates; Obtain white foam shape solid N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-azido-]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine 170mg, yield: 97.4%.
1H?NMR(300MHz，CD 3OD)：δ8.08(s，1H)，7.98(t，J＝1.5Hz，1H)，7.86(t，J＝1.2Hz，1H)，7.42(m，2H)，7.27(m，4H)，7.16(m，1H)，7.06(m，2H)，5.22(m，1H)，4.40(m，1H)，3.85(m，1H)，3.32(m，5H)，2.96-3.06(m，2H)，2.95(s，3H)，1.57(d，J＝6.9Hz，3H)；
13C?NMR(100MHz，CDCl 3)：δ166.1，164.8，161.9(d，J＝245Hz，1C)，157.3，142.1，138.8，137.7，136.0，135.5，129.2，128.6，127.9，127.8，127.7，127.5，126.6，124.2，115.5，115.3，80.3，71.4，53.6，49.1，44.5，38.0，37.9，35.6，28.3，21.8；
LC-MS：m/z?583.0[M+H] +；
[α] D 20＝-79.2°(c?0.5，MeOH)。
According to synthetic route 1, with triazo-compound N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-azido-]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine (29mg; 0.05mmol) and cyclopropyl acethlene (17 μ L 0.2mmol) join in the water of THF and 200 μ L of 800 μ L, after stirring; Add 0.2 normal anti-sepsis acid sodium (2mg; 0.01mmol), 0.2 normal cuprous iodide (1mg, 0.005mmol).Be reflected under the condition of 50 ℃ of heating and react 12-24h, directly obtain end product, yield: 91.5% through TLC (thin-layer chromatography, thin plate chromatography) chromatography.
Figure BSA00000394448800161
1H?NMR(300MHz，CD 3OD)：δ8.29(m，1H)，8.14(m，1H)，7.97(m，1H)，7.89(m，1H)，7.76(m，2H)，7.37-7.44(m，4H)，7.21-7.33(m，5H)，7.15(m，1H)，7.06(m，2H)，5.23(m，1H)，4.57-4.63(m，1H)，4.39-4.53(m，2H)，4.20(m，1H)，3.34(s，3H)，2.99-3.12(m，2H)，2.94(s，3H)，1.57(d，J＝6.7Hz，3H)；
13C?NMR(100MHz，CDCl 3)：δ166.2，164.8，161.9(d，J＝245Hz，1C)，147.3，142.1，138.7，137.4，135.8，135.3，129.7，129.3，128.8，128.7，128.3，128.0，127.9，126.8，125.4，124.0，121.4，115.6，115.4，70.4，54.7，54.1，49.2，38.0，37.9，35.6，21.7；
LC-MS：m/z?685.2[M+H] +；
[α] D 17＝-60.7°(c?0.95，MeOH)。
Embodiment 2:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-cyclohexyl methyl-1,2,3-triazoles base)-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
The synthetic technology route is with reference to described in the embodiment 1, just with cyclohexyl methyl alkynes replacement phenylacetylene, yield: 81.2%.
1H?NMR(300MHz，CD 3OD)：δ8.90(d，J＝7.4Hz，1H)，8.32(d，J＝8.9Hz，1H)，8.12(t，J＝1.6Hz，1H)，7.99(t，J＝1.6Hz，1H)，7.89(t，J＝1.6Hz，1H)，7.74(s，1H)，7.42(m，2H)，7.20-7.28(m，4H)，7.16(m，1H)，7.06(m，2H)，5.24(m，1H)，4.30-4.54(m，3H)，4.13(m，1H)，3.34(s，3H)，2.96-3.10(m，2H)，2.95(s，3H)，2.53(d，J＝6.8Hz，2H)，1.67(m，5H)，1.57(d，J＝7.2Hz，3H)，1.33-1.30(m，4H)，0.89-1.00(m，2H)；
LC-MS：m/z?705.3[M+H] +；
[α] D 23＝-63.4°(c?0.70，MeOH)。
Embodiment 3:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-ethoxycarbonyl-1,2,3-triazoles base)-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800172
The synthetic technology route is just replaced phenylacetylene with ethyl propiolate, yield: 72.4% with reference to described in the embodiment 1.
1H?NMR(300MHz，CD 3OD)：δ8.95(d，J＝8.6Hz，1H)，8.51(s，1H)，8.37(d，J＝9.0Hz，1H)，8.12(m，1H)，7.99(m，1H)，7.88(m，1H)，7.43(m，2H)，7.21-7.30(m，4H)，7.02-7.15(m，3H)，5.23(m，1H)，4.51(m，1H)，4.47(m，2H)，4.35(m，2H)，4.17(m，2H)，3.34(s，3H)，2.97-3.12(m，2H)，2.94(s，3H)，1.57(d，J＝7.0Hz，3H)，1.35(t.J＝7.0Hz，3H)；
13C?NMR(100MHz，CDCl 3)：δ166.3，164.9，161.9(d，J＝245Hz，1C)，160.6，142.1，139.5，138.7，137.3，135.8，135.3，129.3，128.9，128.7，128.0，127.9，126.8，124.0，，115.6，115.4，70.5，61.4，54.8，54.1，49.2，37.9，35.7，21.7，14.2；
LC-MS：m/z681.1[M+H] +；
[α] D 15＝-63.8°(c?0.50，MeOH)。
Embodiment 4:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(N, N-dimethyl-) aminomethyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800181
The synthetic technology route is just used N with reference to described in the embodiment 1, N-dimethyl-propargylamine replacement phenylacetylene, yield: 85.9%.
1H?NMR(300MHz，CD 3OD)：δ8.15(m，1H)，8.00(m，1H)，7.93(m，1H)，7.66(s，1H)，7.42(m，2H)，7.25-7.33(m，4H)，7.18(m，1H)，7.06(m，2H)，5.23(m，1H)，4.61-4.67(m，1H)，4.44-4.52(m，2H)，4.16(m，1H)，3.67(q，J＝3.8，17.9Hz，2H)，3.13(m，1H)，3.00(m，1H)，2.95(s，3H)，2.21(s，6H)，1.58(d，J＝7.1Hz，3H)；
13C?NMR(100MHz，CDCl 3)：δ165.5，164.5，161.9(d，J＝245Hz，1C)，142.2，138.8，137.4，135.8，135.3，134.7，129.3，128.6，128.0，127.9，127.6，126.7，124.0，，115.5，115.3，71.0，54.4，53.8，50.2，49.1，44.4×2，38.3，37.9，35.5，21.7；
LC-MS：m/z?666.2[M+H] +；
[α] D 17＝-57.8°(c?0.80，MeOH)。
Embodiment 5:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(1-hydroxyl) benzyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
The synthetic technology route is with reference to described in the embodiment 1, yield: 88.7%.
1H?NMR(300MHz，CD 3OD)：δ8.12(m，1H)，7.99(m，1H)，7.87(m，1H)，7.80(m，1H)，7.42(m，4H)，7.20-7.38(m，7H)，7.14(m，1H)，7.05(m，2H)，5.89(s，1H)，5.23(m，1H)，4.50-4.55(m，1H)，4.44(m，1H)，4.30-4.37(m，1H)，4.14(m，1H)，3.33(s，3H)，2.97-3.15(m，2H)，2.94(s，3H)，1.57(d，J＝7.0Hz，3H)；
13C?NMR(100MHz，CDCl 3)：δ166.4，165.0，161.9(d，J＝245Hz，1C)，150.8，142.0，141.7，138.7，137.4，135.8，135.3，134.7，129.2，128.6，128.5，128.0，126.7，126.3，126.2，124.3，123.5，123.1，115.5，115.3，70.7，68.6，54.4，53.8，49.1，37.8，37.7，35.5，21.6；
LC-MS：m/z?715.0[M+H] +；
[α] D 17＝-60.3°(c?0.70，MeOH)。
Embodiment 6:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(1-hydroxyl-1,3-dimethyl-) butyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800192
The synthetic technology route is with reference to described in the embodiment 1, yield: 76.6%.
1H?NMR(300MHz，CD 3OD)：δ8.13(m，1H)，7.99(m，1H)，7.90(m，1H)，7.83(d，J＝4.7Hz，1H)，7.42(m，2H)，7.20-7.31(m，4H)，7.16(m，1H)，7.06(m，2H)，5.23(m，1H)，4.51-4.57(m，1H)，4.46(m，1H)，4.32-4.40(m，1H)，4.16(m，1H)，3.36(s，3H)，2.97-3.15(m，2H)，2.95(s，3H)，1.76(m，2H)，1.62-1.73(m，1H)，1.58(d，J＝7.1Hz，3H)，1.54(s，3H)，0.87(q，J＝3.8，6.6Hz，3H)，0.78(d，J＝6.3Hz，3H)；
LC-MS：m/z?709.0[M+H] +；
[α] D 17＝-41.8°(c?0.55，MeOH)。
Embodiment 7:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(2-hydroxyl) propyl group-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800201
The synthetic technology route is with reference to described in the embodiment 1, yield: 78.9%.
1H?NMR(300MHz，CD 3OD)：δ8.15(m，1H)，8.00(m，1H)，7.90(m，1H)，7.78(s，1H)，7.42(m，2H)，7.23-7.30(m，4H)，7.17(m，1H)，7.05(m，2H)，5.24(m，1H)，4.43-4.56(m，2H)，4.31-4.39(m，1H)，4.15(m，1H)，4.01(m，1H)，3.34(s，3H)，2.97-3.12(m，2H)，2.95(s，3H)，2.78(d，J＝5.9Hz，2H)，1.57(d，J＝7.0Hz，3H)，1.18(d，J＝6.1Hz，3H)；
LC-MS：m/z?667.2[M+H] +；
[α] D 23＝-52.1°(c?1.00，MeOH)。
Embodiment 8:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(1-hydroxyl) cyclopentyl-1,2,3-triazoles base)-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800202
The synthetic technology route is with reference to described in the embodiment 1, yield: 88.8%.
1H?NMR(300MHz，CD 3OD)：δ8.13(s，1H)，7.99(s，1H)，7.89(s，1H)，7.86(s，1H)，7.42(m，2H)，7.21-7.31(m，4H)，7.15(m，1H)，7.06(m，2H)，5.23(m，1H)，4.50-4.56(m，1H)，4.46(m，1H)，4.32-4.39(m，1H)，4.16(m，1H)，3.35(s，3H)，2.96-3.12(m，2H)，2.95(s，3H)，1.90-2.05(m，2H)，1.70-1.85(m，4H)，133-1.65(m，7H)；
13C?NMR(100MHz，CDCl 3)：δ166.3，164.9，161.9(d，J＝245Hz，1C)，154.5，142.1，138.8，137.4，135.8，135.3，129.2，128.6，128.0，127.9，126.7，124.3，121.9，115.5，115.3，70.5，69.2，54.4，53.9，49.1，37.9，37.8，37.7，37.5，35.6，25.3，21.9，21.8，21.7；
LC-MS：m/z?707.0[M+H] +；
HRMS：calcd?for?C 36H 43FN 6O 6SNa?729.2847，found?C 36H 43FN 6O 6SNa?729.2836；
[α] D 17＝-64.8°(c?0.50，MeOH)。
Embodiment 9:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800211
According to synthetic route 1, the triazo-compound N-that will make with reference to embodiment 1 [(1S, 2S)-1-benzyl-2-hydroxyl-3-azido-]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine (29mg; 0.05mmol) and the silica-based acetylene of front three (28 μ L 0.2mmol) join in the water of THF and 200 μ L of 800 μ L, after stirring; Add 0.2 normal anti-sepsis acid sodium (2mg; 0.01mmol), 0.1 normal cupric sulfate pentahydrate (1mg, 0.005mmol).Be reflected under the condition of 50 ℃ of heating and react 12-24h, after reaction finishes solvent is concentrated, directly carry out next step reaction.The THF that in above-mentioned system, adds 1mL, tetrabutyl ammonium fluoride Bu 4NF (52mg, 0.2mmol), spend the night, and directly obtains end product 21mg through the TLC chromatography, yield: 70.0% by reaction.
1H?NMR(300MHz，CD 3OD)：δ8.14(m，1H)，8.00(m，2H)，7.89(m，1H)，7.70(s，1H)，7.42(m，2H)，7.21-7.30(m，4H)，7.02-7.15(m，3H)，5.23(m，1H)，4.57-4.63(m，1H)，4.37-4.50(m，2H)，4.17(m，2H)，3.34(s，3H)，2.99-3.12(m，2H)，2.95(s，3H)，1.57(d，J＝7.0Hz，3H)；
LC-MS：m/z?609.1[M+H] +；
HRMS：calcd?for?C 30H 33FN 6O 5SNa?631.2115，found?C 30H 33FN 6O 5SNa?631.2114；
[α] D 17＝-34.0°(c?0.35，MeOH)。
Embodiment 10:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-cyclopropyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
According to synthetic route 1, the triazo-compound N-that will make with reference to embodiment 1 [(1S, 2S)-1-benzyl-2-hydroxyl-3-azido-]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine (29mg; 0.05mmol) and cyclopropyl acethlene (17 μ L 0.2mmol) join in the water of THF and 200 μ L of 800 μ L, after stirring; Add 0.2 normal anti-sepsis acid sodium (2mg; 0.01mmol), 0.1 normal cupric sulfate pentahydrate (1mg, 0.005mmol).Be reflected under the condition of 50 ℃ of heating and react 12-24h, directly obtain end product 23mg, yield: 71.5% through the TLC chromatography.
1H?NMR(300MHz，CD 3OD)：δ8.12(m，1H)，7.99(m，1H)，7.89(m，1H)，7.68(s，1H)，7.42(m，2H)，7.26(m，4H)，7.15(m，1H)，7.05(m，2H)，5.23(m，1H)，4.45(m，2H)，4.32(m，1H)，4.13(m，1H)，3.34(s，3H)，2.97-3.12(m，2H)，2.95(s，3H)，1.56(d，J＝7.1Hz，3H)，1.92(m，1H)，0.92(m，2H)，0.72(m，2H)；
LC-MS：m/z?649.2[M+H] +；
[α] D 15＝-291°(c?0.15，MeOH)。
Embodiment 11:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-isobutyl--1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800221
The synthetic technology route is with reference to described in the embodiment 10, with 4-methyl-1-pentene alkynes (17 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 74.8%.
1H?NMR(300MHz，CD 3OD)：δ8.90(d，J＝7.8Hz，1H)，8.32(d，J＝9.3Hz，1H)，8.12(m，1H)，8.00(t，J＝1.6Hz，1H)，7.89(t，J＝1.6Hz，1H)，7.74(s，1H)，7.42(m，2H)，7.20-7.28(m，4H)，7.16(m，1H)，7.05(m，2H)，5.23(m，1H)，4.48-4.54(m，1H)，4.30-4.46(m，2H)，4.14(m，1H)，3.34(s，3H)，2.97-3.10(m，2H)，2.95(s，3H)，2.53(d，J＝7.1Hz，2H)，1.83-1.97(m，1H)，1.56(d，J＝7.2Hz，3H)，0.91(d，J＝6.8Hz，6H)；
LC-MS：m/z?665.2[M+H] +；
[α] D 15＝-291°(c?0.15，MeOH)。
Embodiment 12:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-methylol-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800231
The synthetic technology route is with reference to described in the embodiment 10, with propynol (12 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 70.1%.
1H?NMR(300MHz，CD 3OD)：δ8.12(m，1H)，7.99(m，1H)，7.94(s，1H)，7.89(m，1H)，7.43(m，2H)，7.21-7.30(m，4H)，7.17(m，1H)，7.05(m，2H)，5.23(m，1H)，4.66(s，2H)，4.53-4.59(m，1H)，4.45-4.49(m，1H)，4.33-4.41(m，1H)，4.15(m，1H)，3.35(s，3H)，2.99-3.12(m，2H)，2.96(s，3H)，1.58(d，J＝7.0Hz，3H)；
LC-MS：m/z?639.1[M+H] +；
[α] D 15＝-107°(c?0.15，MeOH)。
Embodiment 13:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-acetoxy-methyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800232
The synthetic technology route is with reference to described in the embodiment 10, with propargyl acetate (29 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 65.2%.
1H?NMR(300MHz，CD 3OD)：δ8.12(m，1H)，8.01(s，1H)，7.99(m，1H)，7.89(m，1H)，7.43(m，2H)，7.12-7.30(m，4H)，7.15(m，1H)，7.05(m，2H)，5.23(m，1H)，5.14(s，2H)，4.57(m，1H)，4.46(m，2H)，4.16(m，1H)，3.34(s，3H)，2.97-3.12(m，2H)，2.94(s，3H)，2.03(s，3H)，1.57(d，J＝7.1Hz，3H)；
LC-MS：m/z?681[M+H] +；
[α] D 17＝-76.3°(c?0.40，MeOH)。
Embodiment 14:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-Phenoxymethyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
The synthetic technology route is with reference to described in the embodiment 10, with phenyl propargyl ether (26 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 86.4%.
1H?NMR(300MHz，CD 3OD)：δ8.12(m，1H)，8.01(s，1H)，7.99(m，1H)，7.89(m，1H)，7.43(m，2H)，7.12-7.30(m，4H)，7.15(m，1H)，7.05(m，2H)，5.23(m，1H)，5.11(s，2H)，4.57(m，1H)，4.34-4.48(m，2H)，4.16(m，1H)，3.33(s，3H)，2.97-3.12(m，2H)，2.94(s，3H)，2.03(s，3H)，1.56(d，J＝7.2Hz，3H)；
13C?NMR(100MHz，CDCl 3)：δ166.3，164.8，161.9(d，J＝245Hz，1C)，158.0，143.9，142.2，138.7，137.3，135.8，135.3，129.6，129.2，128.7，128.0，127.9，127.8，126.8，124.5，124.0，121.4，115.6，115.4，114.6，70.6，61.5，54.4，54.1，49.2，37.9，37.7，35.7，21.7；
LC-MS：m/z?715.1[M+H] +；
[α] D 15＝-67.8°(c?0.60，MeOH)。
Embodiment 15:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(5-phenyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800242
Carry out according to synthetic route 2:
Triazo-compound the N-[(1S that will make with reference to embodiment 1; 2S)-1-benzyl-2-hydroxyl-3-azido-]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine (29mg; 0.05mmol) and phenylacetylene (22 μ L, 0.2mmol) and Ru (PPh 3) 2Cl 2(4mg 0.005mmol) joins among the THF of 1mL, and the protection refluxed reaction 8h at argon gas directly obtains end product 20mg through the TLC chromatography, yield: 58.8%.
1H?NMR(300MHz，CD 3OD)：δ7.99(m，2H)，7.78(m，1H)，7.74(s，1H)，7.41-7.48(m，4H)，7.21-7.31(m，7H)，7.17(m，1H)，7.06(m，2H)，5.23(m，1H)，4.44-4.49(m，1H)，4.26-4.42(m，3H)，3.34(s，3H)，2.96-3.07(m，2H)，2.95(s，3H)，1.57(d，J＝7.1Hz，3H)；
LC-MS：m/z685.2[M+H] +；
[α] D 15＝-90.3°(c?0.35，MeOH).
Embodiment 16:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(5-ethoxy acyl group-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800251
The synthetic technology route is with reference to described in the embodiment 15, with ethyl propiolate (20 μ L, 0.2mmol) replacement phenylacetylene, yield: 46.3%.
1H?NMR(300MHz，CD 3OD)：δ8.16(s，1H)，8.15(m，1H)，8.00(m，1H)，7.94(m，1H)，7.42(m，2H)，7.21-7.31(m，4H)，7.17(m，1H)，7.06(m，2H)，5.23(m，1H)，4.85(m，2H)，4.44(m，1H)，4.26(m，2H)，3.37(s，3H)，2.99-3.11(m，2H)，2.97(s，3H)，1.58(d，J＝7.1Hz，3H)，1.28(t，J＝7.0Hz，3H)；
LC-MS：m/z?681.0[M+H] +；
[α] D 17＝-61.0°(c?0.30，MeOH)
Embodiment 17:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(5-methylol-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800252
The synthetic technology route is with reference to described in the embodiment 15, with propynol (12 μ L, 0.2mmol) replacement phenylacetylene, yield: 51.1%.
1H?NMR(300MHz，CD 3OD)：δ8.12(m，1H)，7.99(m，1H)，7.88(m，1H)，7.63(s，1H)，7.42(m，2H)，7.22-7.32(m，4H)，7.17(m，1H)，7.06(m，2H)，5.23(m，1H)，4.72(q，J＝13.5，21.6Hz，2H)，4.57-4.64(m，1H)，4.42-4.53(m，2H)，4.25(m，1H)，3.36(s，3H)，2.99-3.14(m，2H)，2.96(s，3H)，1.58(d，J＝7.1Hz，3H)；
LC-MS：m/z?639.1[M+H] +；
[α] D 17＝-58.0°(c?0.20，MeOH)。
Embodiment 18:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(5-Phenoxymethyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800261
The synthetic technology route is with reference to described in the embodiment 15, with phenyl propargyl ether (26 μ L, 0.2mmol) replacement phenylacetylene, yield: 50.6%.
1H?NMR(300MHz，CD 3OD)：δ8.08(m，1H)，7.98(m，1H)，7.85(m，1H)，7.74(s，1H)，7.42(m，2H)，7.20-7.29(m，4H)，7.02-7.17(m，5H)，6.84(m，3H)，5.23(m，3H)，4.57-4.64(m，1H)，4.42-4.50(m，2H)，4.26(m，1H)，3.31(s，3H)，2.91-3.14(m，2H)，2.91(s，3H)，1.57(d，J＝7.1Hz，3H)；
LC-MS：m/z?715.2[M+H] +；
[α] D 15＝-57.0°(c?0.20，MeOH)。
Embodiment 19:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-methoxy ethanoyl-5-methoxy ethanoyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800262
Carry out according to synthetic route 3:
Triazo-compound the N-[(1S that will make with reference to embodiment 1; 2S)-1-benzyl-2-hydroxyl-3-azido-]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine (29mg; 0.05mmol) and dimethyl butyn (24 μ L 0.2mmol) join in the toluene of 1mL.Be reflected under the condition of 100 ℃ of heating and react 24h, directly obtain end product 24mg, yield: 66.3% through the TLC chromatography.
Figure BSA00000394448800271
1H?NMR(300MHz，CD 3OD)：δ8.11(t，J＝1.5Hz，1H)，8.00(t，J＝1.5Hz，1H)，7.91(t，J＝1.5Hz，1H)，7.41-7.51(m，2H)，7.23-7.34(m，4H)，7.17(m，1H)，7.01-7.09(m，2H)，5.24(q，J＝7.6，14.3Hz，1H)，4.64-4.80(m，2H)，4.43-4.60(m，1H)，4.11(m，1H)，3.80-3.95(m，6H)，3.38(s，3H)，2.94-3.10(m，5H)，1.57-1.63(m，3H)；
LC-MS：m/z?725.0[M+H] +；
[α] D 15＝-17.6°(c?1.30，MeOH)。
Embodiment 20:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-methylol-5-methylol-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800272
The synthetic technology route is with reference to described in the embodiment 19, and with 2-butyne-1, (16mg 0.2mmol) replaces dimethyl butyn, yield: 55.6% to the 4-glycol.
1H?NMR(300MHz，CD 3OD)：δ8.11(m，1H)，7.99(m，1H)，7.88(m，1H)，7.42(m，2H)，7.22-7.31(m，4H)，7.16(m，1H)，7.06(m，2H)，5.23(m，1H)，4.66-4.81(m，4H)，4.56-4.62(m，1H)，4.43-4.57(m，2H)，4.25(m，1H)，3.35(s，3H)，2.98-3.13(m，2H)，2.96(s，3H)，2.57(s，3H)，1.57(d，J＝7.2Hz，3H)；
LC-MS：m/z?669.1[M+H] +；
[α] D 15＝-56.0°(c?0.20，MeOH)。
Embodiment 21:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-methylol-5-benzyloxymethyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800273
Embodiment 22:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-benzyloxymethyl-5-methylol-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800281
The synthesis step of compound is with embodiment 19 among the embodiment 21 and 22, and just with 4-benzyloxy-2-butyne-1-alcohol replacement dimethyl butyn, wherein, the synthetic route of 4-benzyloxy-2-butyne-1-alcohol is following:
Figure BSA00000394448800282
4-benzyloxy-2-butyne-1-alcohol synthetic: with Pottasium Hydroxide (3.67g 67mmol) is dissolved in the water of 50mL, adds 1 respectively, the 4-butynediol (5.78g, 67.2mmol) with the benzyl bromine (2mL, 16.8mmol), room temperature reaction 48h.Add dichloromethane extraction (40mL * 3), merge organic phase, organic phase is with saturated common salt washing (20mL * 1), and anhydrous magnesium sulfate drying filters, and concentrates, and crosses post with petrol ether/ethyl acetate=1/5 and gets colorless oil 2.0g, yield: 67.7%.
1H?NMR(300MHz，CDCl3)：δ7.25(m，5H)，4.60(s，2H)，4.32(m，2H)，4.22(m，2H)。
(34mg 0.2mmol) replaces dimethyl butyn, from reaction solution, is separated to positional isomers 172:13mg, 173:14mg simultaneously, and yield is respectively: 34.3%, 36.9% with 4-benzyloxy-2-butyne-1-alcohol.
1H?NMR(300MHz，CD 3OD)：δ8.11(m，1H)，7.99(m，1H)，7.90(m，1H)，7.42(m，2H)，7.20-7.30(m，10H)，7.06(m，2H)，5.24(m，1H)，4.59-4.82(m，5H)，4.39-4.54(m，4H)，4.26(m，1H)，3.32(s，3H)，2.99-3.13(m，2H)，2.92(s，3H)，1.57(d，J＝7.1Hz，3H)；
LC-MS：m/z?759.1[M+H] +；
[α] D 17＝-71.2°(c?0.25，MeOH)。
1H?NMR(300MHz，CD 3OD)：δ8.13(m，1H)，7.99(m，1H)，7.88(m，1H)，7.42(m，2H)，7.22-7.34(m，9H)，7.17(m，1H)，7.06(m，2H)，5.23(m，1H)，4.57-4.78(m，5H)，4.46-4.54(m，4H)，4.26(m，1H)，3.35(s，3H)，2.99-3.13(m，2H)，2.95(s，3H)，1.58(d，J＝7.0Hz，3H)；
LC-MS：m/z?759.1[M+H] +；
[α] D 17＝-37.0°(c?0.10，MeOH)。
Embodiment 23:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(1-hydroxyethyl) 5-iodo-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800291
N-iodo morpholine hydriodate synthetic: iodine (25.4,0.10mmol) be dissolved in the methyl alcohol of 400mL, progressively splash into morpholine (8.71mL, 0.10mol).In the process that drips, solution is become faint yellow by dark-brown, and has the xanchromatic deposition to separate out.After dropwising, at room temperature continue reaction 1h.Filter, the solid that obtains is product, and dried in vacuum gets product 26.8g, yield: 78.7%.
4-iodo-3-butyne-2-alcohol synthetic: the 3-butyne-2-alcohol (560mg 8mmol) is dissolved among the 20mLTHF, add cuprous iodide (76mg, 0.4mmol) with N-iodo morpholine hydriodate (3.0g, 8.8mmol).2h is at room temperature carried out in reaction.Diatomite filtration, concentrate yellow oil product 1.2g, yield: 76.9%.
1H?NMR(300MHz，CDCl3)：δ6.62(q，J＝13.2，6.68Hz，1H)，1.47(s，1.5H)，1.45(s，1.5H)。
According to synthetic route 1, the triazo-compound N-that will make with reference to embodiment 1 [(1S, 2S)-1-benzyl-2-hydroxyl-3-azido-]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine (582mg; 1mmol) with 4-iodo-3-butyne-2-alcohol (220mg; 1.1mmol) be dissolved among the THF of 5mL, add subsequently cuprous iodide (10mg, 0.05mmol) and triethylamine (0.28mL; 2.00mmol), reaction is at room temperature spent the night.Concentrate, add water (20mL), dichloromethane extraction (20mL * 3) merges organic phase, and with the saturated common salt washing, anhydrous sodium sulfate drying filters, and concentrates, and crosses post with petrol ether/ethyl acetate=1/1-0/1, obtains the solid 550mg of white, yield: 70.7%.Fusing point: 100-103 ℃.
Figure BSA00000394448800292
1H?NMR(300MHz，CD 3OD)：δ8.17(m，1H)，8.00(m，1H)，7.94(m，1H)，7.42(m，2H)，7.21-7.31(m，4H)，7.16(m，1H)，7.06(m，2H)，5.23(m，1H)，4.89-4.90(m，1H)，4.41-4.52(m，3H)，4.26-4.34(m，1H)，3.35(s，3H)，2.99-3.14(m，2H)，1.56(m，6H)；
LC-MS：m/z?778.9[M+H] +；
[α] D 15＝-52.0°(c?0.90，MeOH)。
Embodiment 24:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(3-aminomethyl phenyl)-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800301
The synthetic technology route is with reference to described in the embodiment 10, with 3-methylbenzene acetylene (26 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 91.5%.
1H?NMR(300MHz，CD 3OD)：δ8.27(m，1H)，8.14(m，1H)，7.98(m，1H)，7.88(m，1H)，7.57(m，2H)，7.45(m，2H)，7.21-7.31(m，5H)，7.15(m，2H)，7.05(m，2H)，5.23(m，1H)，3.98-4.62(m，3H)，4.22(m，1H)，3.34(s，3H)，2.97-3.15(m，2H)，2.94(s，3H)，2.36(s，3H)，1.57(d，J＝7.3Hz，3H)；
13C?NMR(100MHz，CDCl 3)：δ166.2，164.8，161.9(d，J＝245Hz，1C)，147.5，142.1，138.7，138.4，137.4，135.8，135.3，129.6，129.3，129.0，128.6，128.0，127.9，127.8，126.7，126.1，124.0，122.5，121.4，115.5，115.3，70.5，54.6，54.1，49.2，38.0，37.8，35.6，21.7，21.3；
LC-MS：m/z?699.2[M+H] +；
[α] D 18＝-63.3°(c?1.20，MeOH)。
Embodiment 25:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(4-fluorophenyl)-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
The synthetic technology route is with reference to described in the embodiment 10, with 4-fluorobenzene acetylene (23 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 94.2%.
1H?NMR(300MHz，CD 3OD)：δ8.26(s，1H)，8.12(m，1H)，7.98(m，1H)，7.89(m，1H)，7.56-7.80(m，2H)，7.43(m，2H)，7.21-7.31(m，4H)，7.14(m，3H)，7.06(m，2H)，5.23(m，1H)，4.57-4.63(m，1H)，4.39-4.52(m，2H)，4.22(m，1H)，3.34(s，3H)，2.97-3.15(m，2H)，2.95(s，3H)，1.58(d，J＝7.1Hz，3H)；
LC-MS：m/z?703.1[M+H] +；
[α] D 18＝-58.8°(c?1.15，MeOH)。
Embodiment 26:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(4-p-methoxy-phenyl)-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800311
The synthetic technology route is with reference to described in the embodiment 10, with 4-anisole acetylene (26 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 90.2%.
1H?NMR(300MHz，CD 3OD)：δ8.19(s，1H)，8.12(m，1H)，7.98(m，1H)，7.88(m，1H)，7.66(m，2H)，7.43(m，2H)，7.21-7.31(m，4H)，7.14(m，1H)，7.06(m，2H)，6.95(m，2H)，5.23(m，1H)，4.57-4.63(m，1H)，4.39-4.52(m，2H)，4.22(m，1H)，3.81(s，3H)，3.33(s，3H)，2.97-3.15(m，2H)，2.95(s，3H)，1.58(d，J＝7.0Hz，3H)；
LC-MS：m/z?715.1[M+H] +；
[α] D 18＝-52.6°(c?1.10，MeOH)。
Embodiment 27:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(2-pyridyl)-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800312
The synthetic technology route is with reference to described in the embodiment 10, with pyridine-2-acetylene (20 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 82.1%.
1H?NMR(300MHz，CD 3OD)：δ8.47(s，1H)，8.13(m，1H)，7.98(m，2H)，7.89(m，2H)，7.43(m，2H)，7.22-7.37(m，5H)，7.16(m，1H)，5.23(m，1H)，4.63-4.69(m，1H)，4.42-4.55(m，2H)，4.22(m，1H)，3.35(s，3H)，2.97-3.15(m，2H)，2.95(s，3H)，1.58(d，J＝7.0Hz，3H)；
LC-MS：m/z?686.2[M+H] +；
[α] D 17＝-34.0°(c?0.35，MeOH)。
Embodiment 28:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(the 4-tertiary butyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800321
The synthetic technology route is with reference to described in the embodiment 10, with tertiary butyl acetylene (25 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 82.3%.
1H?NMR(300MHz，CD 30D)：δ8.13(m，1H)，7.99(m，1H)，7.89(m，1H)，7.74(s，1H)，7.42(m，2H)，7.21-7.29(m，4H)，7.15(m，1H)，7.05(m，2H)，5.23(m，1H)，4.46-4.54(m，1H)，4.45(m，1H)，4.29-4.37(m，1H)，4.15(m，1H)，3.35(s，3H)，2.97-3.12(m，2H)，2.95(s，3H)，1.57(d，J＝7.0Hz，3H)，1.31(s，9H)；
13C?NMR(100MHz，CDCl 3)：δ166.3，164.9，161.9(d，J＝245Hz，1C)，157.4，142.1，138.8，137.4，135.8，135.3，129.3，128.6，128.0，127.9，127.8，126.7，124.1，120.5，115.6，115.3，70.3，54.2，54.1，49.2，37.9，37.7，35.6，30.6，30.2，21.7；
LC-MS：m/z?665.2[M+H] +；
HRMS：calcd?for?C 34H 41FN 6O 5SNa?687.2741，found?C 34H 41FN 6O 5SNa?687.2738；
[α] D 15＝-68.1°(c?0.75，MeOH)。
Embodiment 29:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-sec.-propyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800322
The synthetic technology route is with reference to described in the embodiment 10, with 3-methyl isophthalic acid-acetylene (19 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 64.5%.
1H?NMR(300MHz，CD 3OD)：δ8.90(d，J＝8.2Hz，1H)，8.32(d，J＝8.9Hz，1H)，8.12(m，1H)，7.99(m，1H)，7.89(m，1H)，7.74(s，1H)，7.42(m，2H)，7.21-7.30(m，4H)，7.16(m，1H)，7.05(m，2H)，5.23(m，1H)，4.41-4，54(m，2H)，4.29-4.37(m，1H)，4.14(m，1H)，3.34(s，3H)，2.97-3.10(m，3H)，2.94(s，3H)，1.56(d，J＝7.3Hz，3H)，1.26(d.J＝6.8Hz，6H)；
13C?NMR(100MHz，CDCl 3)：δ166.2，164.8，161.9(d，J＝245Hz，1C)，154.2，142.2，138.7，137.4，135.8，135.3，129.3，128.6，128.0，127.9，127.8，126.7，124.0，121.1，115.5，115.3，70.4，54.3，54.2，49.2，37.9，37.7，35.6，25.6，22.3，22.2，21.7；
LC-MS：m/z?651.1[M+H] +；
HRMS：calcd?for?C 33H 39FN 6O 5SNa?673.2584，found?C 33H 39FN 6O 5SNa?673.2591；
[α] D 17＝-55.3°(c?0.80，MeOH)。
Embodiment 30:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-propyl group-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800331
The synthetic technology route is with reference to described in the embodiment 10, with 1-pentyne (20 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 62.7%.
1H?NMR(300MHz，CD 3OD)：δ8.12(m，1H)，7.99(m，1H)，7.89(m，1H)，7.75(s，1H)，7.42(m，2H)，7.26(m，4H)，7.15(m，1H)，7.06(m，2H)，5.24(m，1H)，4.45(m，2H)，4.32(m，1H)，4.13(m，1H)，3.36(s，3H)，2.97-3.12(m，2H)，2.96(s，3H)，2.64(t，J＝7.6Hz，2H)，1.66(m，2H)，1.58(d，J＝7.1Hz，3H)，0.96(t，J＝7.3Hz，3H)；
LC-MS：m/z?651.2[M+H] +；
HRMS：calcd?for?C 33H 39FN 6O 5SNa?673.2584，found?C 33H 39FN 6O 5SNa?673.2595；
[α] D 15＝-33.0°(c?0.15，MeOH)。
Embodiment 31:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-cyclopentyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
The synthetic technology route is with reference to described in the embodiment 10, with cyclopentyl acetylene (23 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 86.2%.
1H?NMR(300MHz，CD 3OD)：δ8.91(d，J＝8.2Hz，1H)，8.32(d，J＝8.8Hz，1H)，8.12(s，1H)，7.99(s，1H)，7.89(s，1H)，7.74(s，1H)，7.42(m，2H)，7.21-7.29(m，4H)，7.15(m，1H)，7.06(m，2H)，5.24(m，1H)，4.40-4.54(m，2H)，4.29-4.37(m，1H)，4.13(m，1H)，3.34(s，3H)，2.96-3.11(m，3H)，2.94(s，3H)，2.05(m，2H)，1.61-1.80(m，6H)，1，1.57(d，J＝6.7Hz，3H)；
LC-MS：m/z?677.2[M+H] +；
[α] D 23＝-35.8°(c?0.50，MeOH)。
Embodiment 32:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-cyclohexyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800341
The synthetic technology route is with reference to described in the embodiment 10, with cyclohexyl-acetylene (26 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 86.2%.
1H?NMR(300MHz，CD 3OD)：δ8.12(m，1H)，8.00(m，1H)，7.89(m，1H)，7.72(s，1H)，7.42(m，2H)，7.21-7.29(m，4H)，7.15(m，1H)，7.06(m，2H)，5.23(m，1H)，4.40-4.54(m，2H)，4.30-4.37(m，1H)，4.15(m，1H)，3.35(s，3H)，2.98-3.11(m，2H)，2.96(s，3H)，2.68(m，1H)，1.98(m，2H)，1.80(m，3H)，1.57(d，J＝7.0Hz，3H)，1.25-1.45(m，5H)；
LC-MS：m/z691.2[M+H] +；
[α] D 17＝-86°(c?0.30，MeOH)。
Embodiment 33:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(2-hydroxyethyl)-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800342
The synthetic technology route is with reference to described in the embodiment 10, with 3-butine-1-alcohol (15 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 74.3%.
1H?NMR(300MHz，CD 3OD)：δ8.13(s，1H)，7.99(s，1H)，7.89(s，1H)，7.79(s，1H)，7.42(m，2H)，7.21-7.31(m，4H)，7.15(m，1H)，7.06(m，2H)，5.23(m，1H)，4.50-4.56(m，1H)，4.46(m，1H)，4.30-4.38(m，1H)，4.16(m，1H)，3.78(m，2H)，3.35(s，3H)，2.96-3.12(m，2H)，2.95(s，3H)，2.87(t，J＝6.6Hz，2H)，1.57(d，J＝7.0Hz，3H)；
13C?NMR(100MHz，CDCl 3)：δ166.3，164.9，161.9(d，J＝245Hz，1C)，142.0，138.9，137.4，135.9，135.1，129.2，128.6，128.0，127.9，126.8，124.3，115.5，115.2，70.8，61.0，54.3，54.0，53.9，49.1，37.9，37.7，35.6，28.5，21.6；
LC-MS：m/z?653.1[M+H] +；
[α] D 17＝-66.2°(c?0.55，MeOH)。
Embodiment 34:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(3-hydroxypropyl)-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800351
The synthetic technology route is with reference to described in the embodiment 10, with 4-pentyne-1-alcohol (18 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 78.5%.
1H?NMR(300MHz，CD 3OD)：δ8.13(s，1H)，7.99(s，1H)，7.89(s，1H)，7.76(s，1H)，7.42(m，2H)，7.21-7.31(m，4H)，7.15(m，1H)，7.05(m，2H)，5.23(m，1H)，4.49-4.56(m，1H)，4.45(m，1H)，4.30-4.39(m，1H)，4.15(m，1H)，3.58(t，J＝6.0Hz，2H)，3.34(s，3H)，2.96-3.12(m，2H)，2.95(s，3H)，2.74(t，J＝7.5Hz，2H)，1.85(m，2H)，1.57(d，J＝7.3Hz，3H)；
LC-MS：m/z?667.1[M+H] +；
[α] D 18＝-64.0°(c?0.60，MeOH)。
Embodiment 35:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-aminomethyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800361
According to synthetic route 1; The triazo-compound N-that will make with reference to embodiment 1 [(1S, 2S)-1-benzyl-2-hydroxyl-3-azido-]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] (29mg is 0.05mmol) with 2-propargylamine base t-butyl formate (16mg for isophthaloyl amine; 0.1mmol) join in the water of THF and 200 μ L of 800 μ L; After stirring, add 0.2 normal anti-sepsis acid sodium (2mg, 0.01mmol); 0.1 normal cupric sulfate pentahydrate (1mg, 0.005mmol).Be reflected under the condition of 50 ℃ of heating and react 24h, concentrate.Enriched material is dissolved in the methylene dichloride of 1mL, adds the trifluoroacetic acid of 200 μ L, under room temperature, react 2h.Add saturated sodium bicarbonate (10mL), dichloromethane extraction (10mL * 2) concentrates, and directly obtains end product 25mg through the TLC chromatography, yield: 78.1%.
1H?NMR(300MHz，CD 3OD)：δ8.14(s，1H)，8.09(s，1H)，8.00(s，1H)，7.90(s，1H)，7.42(m，2H)，7.20-7.30(m，4H)，7.16(m，1H)，7.05(m，2H)，5.23(q，J＝6.9，13.5Hz，1H)，4.55-4.62(m，1H)，4.34-4.47(m，2H)，4.22(s，3H)，3.34(s，3H)，2.98-3.11(m，2H)，2.96(s，3H)，1.58(d，J＝6.6Hz，3H)；
LC-MS：m/z?638.2[M+H] +；
[α] D 17＝-71.8°(c?0.50，MeOH)。
Embodiment 36:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-ethanoyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800362
The synthetic technology route is with reference to described in the embodiment 10, with 3-crotonylene-ketone (15 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 68.9%.
1H?NMR(300MHz，CD 3OD)：δ8.49(s，1H)，8.11(m，1H)，7.99(m，1H)，7.88(m，1H)，7.42(m，2H)，7.21-7.30(m，4H)，7.16(m，1H)，7.06(m，2H)，5.23(m，1H)，4.60-4.66(m，1H)，4.39-4.51(m，2H)，4.16(m，1H)，3.34(s，3H)，2.99-3.12(m，2H)，2.96(s，3H)，2.57(s，3H)，1.58(d，J＝7.1Hz，3H)；
13C?NMR(100MHz，CDCl 3)：δ192.8，166.3，164.8，161.9(d，J＝245Hz，1C)，147.4，142.1，138.6，137.1，135.7，135.2，129.2，128.7，128.0，127.9，127.3，126.9，124.1，115.6，115.4，70.6，54.6，54.1，49.2，37.9，37.7，35.6，27.1，21.7；
LC-MS：m/z650.9[M+H] +；
[α] D 17＝-71.8°(c?0.50，MeOH)。
Embodiment 37:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(1-hydroxyl-1-methyl) ethyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
The synthetic technology route is with reference to described in the embodiment 10, with 2-methyl-3-butyne-2-alcohol (19 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 80.1%.
1H?NMR(300MHz，CD 3OD)：δ8.14(m，1H)，7.99(m，1H)，7.90(m，1H)，7.85(s，1H)，7.42(m，2H)，7.22-7.31(m，4H)，7.17(m，1H)，7.05(m，2H)，5.23(m，1H)，4.51-4.56(m，1H)，4.46(m，1H)，4.32-4.40(m，1H)，4.16(m，1H)，3.35(s，3H)，2.97-3.15(m，2H)，2.95(s，3H)，1.57(d，J＝7.1Hz，3H)，1.56(s，6H)；
13C?NMR(100MHz，CDCl 3)：δ166.3，165.0，161.9(d，J＝245Hz，1C)，155.0，142.0，138.8，137.4，135.8，135.3，129.3，128.6，128.0，127.9，126.8，124.4，121.5，115.5，115.3，70.6，68.1，54.3，54.0，49.2，37.9，37.8，35.6，30.0，29.8，21.7；
LC-MS：m/z?667.0[M+H] +；
HRMS：calcd?for?C 33H 39FN 6O 6SNa?689.2534，found?C 33H 39FN 6O 6SNa?689.2546；
[α] D 17＝-53.9°(c?0.70，MeOH)。
Embodiment 38:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(1-hydroxyl-1-methyl) propyl group-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800381
The synthetic technology route is with reference to described in the embodiment 10, with methylpentynol (23 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 86.7%.
1H?NMR(300MHz，CD 3OD)：δ8.13(m，1H)，7.99(m，1H)，7.90(m，1H)，7.83(m，1H)，7.42(m，2H)，7.22-7.31(m，4H)，7.17(m，1H)，7.06(m，2H)，5.23(m，1H)，4.51-4.57(m，1H)，4.46(m，1H)，4.32-4.40(m，1H)，4.16(m，1H)，3.35(s，3H)，2.97-3.15(m，2H)，2.95(s，3H)，1.85(q，J＝7.1，14.2Hz，2H)，1.52(s，3H)，1.57(d，J＝7.1Hz，3H)，0.83(t，J＝7.4Hz，3H)；
13C?NMR(100MHz，CDCl 3)：δ166.3，164.9，161.9(d，J＝245Hz，1C)，154.1，142.1，138.8，137.4，135.8，135.3，129.2，128.7，128.0，127.9，126.7，124.3，122.0，115.5，115.3，70.5，54.3，54.0，49.2，37.9，37.7，35.6，35.4，27.0，21.7，8.28；
LC-MS：m/z?663.2[M+H] +；
HRMS：calcd?for?C 34H 41FN 6O 6SNa?703.2690，found?C 34H 41FN 6O 6SNa?730.2687；
[α] D 17＝-70.0°(c?0.50，MeOH)。
Embodiment 39:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(1-hydroxyl-1,2-dimethyl-) propyl group-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800382
The synthetic technology route is with reference to described in the embodiment 10, and with 3, (25 μ L 0.2mmol) replace cyclopropyl acethlene, yield: 85.5% to 4-dimethyl--1-pentyne-3-alcohol.
1H?NMR(300MHz，CD 3OD)：δ8.13(m，1H)，7.99(m，1H)，7.90(m，1H)，7.83(d，J＝5.7Hz，1H)，7.42(m，2H)，7.20-7.29(m，4H)，7.16(m，1H)，7.06(m，2H)，5.23(m，1H)，4.50-4.57(m，1H)，4.44(m，1H)，4.32-4.42(m，1H)，4.16(m，1H)，3.35(s，3H)，2.97-3.15(m，2H)，2.96(s，3H)，2.05(m，1H)，1.58(d，J＝7.0Hz，3H)，1.51(s，3H)，0.87(d，J＝6.7Hz，3H)；
LC-MS：m/z?695.1[M+H] +；
HRMS：calcd?for?C 35H 43FN 6O 6SNa?717.2847，found?C 35H 43FN 6O 6SNa?717.2842；
[α] D 17＝-43.0°(c?0.30，MeOH)。
Embodiment 40:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(1-hydroxycyclopent base)-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800391
The synthetic technology route is with reference to described in the embodiment 10, with 1-ethynyl-1-cyclopentanol (23 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 83.2%.
1H?NMR(300MHz，CD 3OD)：δ8.13(s，1H)，7.99(s，1H)，7.89(s，1H)，7.86(s，1H)，7.42(m，2H)，7.21-7.31(m，4H)，7.15(m，1H)，7.05(m，2H)，5.23(m，1H)，4.50-4.56(m，1H)，4.46(m，1H)，4.32-4.39(m，1H)，4.16(m，1H)，3.34(s，3H)，2.97-3.12(m，2H)，2.95(s，3H)，1.86-2.15(m，6H)，1.79(m，2H)，1.57(d，J＝7.0Hz，3H)；
13C?NMR(100MHz，CDCl 3)：δ166.3，164.9，161.9(d，J＝245Hz，1C)，153.7，142.1，138.8，137.4，135.8，135.3，129.3，128.6，128.0，127.9，126.7，124.3，122.0，115.5，115.3，70.5，54.3，54.0，49.2，40.6，40.4，37.9，37.8，35.6，23.4，21.7；
LC-MS：m/z?692.9[M+H] +；
HRMS：calcd?for?C 35H 41FN 6O 6SNa?715.2690，found?C 35H 41FN 6O 6SNa?715.2704；
[α] D 18＝-59.3°(c?0.75，MeOH)。
Embodiment 41:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(1-hydroxyethyl)-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800392
The synthetic technology route is with reference to described in the embodiment 10, with 3-butyne-2-alcohol (16 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 73.1%.
1H?NMR(300MHz，CD 3OD)：δ8.13(s，1H)，7.99(s，1H)，7.88(s，1H)，7.42(m，2H)，7.22-7.33(m，5H)，7.14(m，1H)，7.10(m，2H)，5.23(m，1H)，4.93(m，1H)，4.51-4.58(m，1H)，4.33-4.50(m，2H)，4.16(m，1H)，3.35(s，3H)，2.97-3.15(m，2H)，2.95(s，3H)，1.57(d，J＝7.0Hz，3H)，1.40(d，J＝6.6Hz，3H)；
13C?NMR(100MHz，CDCl 3)：δ166.3，164.9，161.9(d，J＝245Hz，1C)，142.0，138.7，137.4，135.8，135.3，129.2，128.7，128.0，127.9，126.8，124.3，122.3，115.5，115.3，70.6，61.3，54.3，54.1，49.2，37.9，37.7，35.7，22.9，21.7；
LC-MS：m/z?653.1[M+H] +；
HRMS：calcd?for?C 32H 37FN 6O 6SNa?675.2377，found?C 32H 37FN 6O 6SNa?675.2396；
[α] D 17＝-65.3°(c?0.45，MeOH)。
Embodiment 42:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(1-hydroxypropyl)-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800401
The synthetic technology route is with reference to described in the embodiment 10, with 1-pentyne-3-alcohol (19 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 78.7%.
1H?NMR(300MHz，CD 3OD)：δ8.12(m，1H)，7.99(m，1H)，7.89(m，2H)，7.42(m，2H)，7.20-7.30(m，4H)，7.15(m，1H)，7.06(m，2H)，5.23(m，1H)，4.69(m，1H)，4.52-4.58(m，1H)，4.33-4.48(m，2H)，4.16(m，1H)，3.36(s，3H)，2.99-3.13(m，2H)，2.96(s，3H)，1.83(m，2H)，1.58(d，J＝7.0Hz，3H)，0.94(t，J＝7.4Hz，3H)；
LC-MS：m/z?667.1[M+H] +；
HRMS：calcd?for?C 33H 39FN 6O 6SNa?689.2534，found?C 33H 39FN 6O 6SNa?689.2530；
[α] D 17＝-20.0°(c?0.25，MeOH)。
Embodiment 43:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(1-hydroxybutyl)-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800411
The synthetic technology route is with reference to described in the embodiment 10, with 1-hexin-3-alcohol (19 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 80.1%.
1H?NMR(300MHz，CD 3OD)：δ8.12(m，1H)，7.99(m，1H)，7.88(m，2H)，7.42(m，2H)，7.20-7.30(m，4H)，7.15(m，1H)，7.06(m，2H)，5.23(m，1H)，4.77(t，J＝6.9Hz，1H)，4.52-4.58(m，1H)，4.33-4.48(m，2H)，4.16(m，1H)，3.36(s，3H)，2.99-3.13(m，2H)，2.96(s，3H)，1.78(a，J＝6.7，14.4Hz，2H)，1.58(d，J＝7.0Hz，3H)，1.30-1.52(m，2H)，0.95(t，J＝7.4Hz，3H)；
13C?NMR(100MHz，CDCl 3)：δ166.4，165.0，161.9(d，J＝245Hz，1C)，142.0，138.7，137.4，135.8，135.3，129.2，128.7，128.0，127.9，126.8，124.4，122.6，115.5，115.3，70.6，66.5，54.3，53.9，50.7，49.1，37.9，37.7，36.7，35.6，27.6，22.4，21.6；
LC-MS：m/z?681.1[M+H] +；
HRMS：calcd?for?C 34H 41FN 6O 6SNa?703.2690，found?C 34H 41FN 6O 6SNa?703.2674；
[α] D 17＝-62.0°(c?0.30，MeOH)。
Embodiment 44:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(1-hydroxy-2-methyl) propyl group)-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800412
The synthetic technology route is with reference to described in the embodiment 10, with 4-methyl-1-pentene alkynes-3-alcohol (21 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 76.3%.
1H?NMR(300MHz，CD 3OD)：δ8.12(m，1H)，7.99(m，1H)，7.87(m，2H)，7.42(m，2H)，7.20-7.30(m，4H)，7.15(m，1H)，7.06(m，2H)，5.24(m，1H)，4.52-4.58(m，2H)，4.33-4.48(m，2H)，4.16(m，1H)，3.36(s，3H)，2.99-3.13(m，2H)，2.96(s，3H)，2.04(m，1H)，1.78(a，J＝6.7，14.4Hz，2H)，1.58(d，J＝7.3Hz，3H)，0.94(d，J＝6.7Hz，3H)，0.87(t，J＝6.7Hz，3H)；
LC-MS：m/z?681.1[M+H] +；
HRMS：calcd?for?C 34H 41FN 6O 6SNa?703.2690，found?C 34H 41FN 6O 6SNa?703.2702；
[α] D 17＝-17.0°(c?0.20，MeOH)。
Embodiment 45:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(1-hydroxyl amyl group)-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800421
The synthetic technology route is with reference to described in the embodiment 10, with 1-heptyne-3-alcohol (26 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 81.2%.
1H?NMR(300MHz，CD 3OD)：δ8.12(m，1H)，7.99(m，1H)，7.87(m，2H)，7.42(m，2H)，7.20-7.30(m，4H)，7.15(m，1H)，7.06(m，2H)，5.23(m，1H)，4.75(t，J＝6.5Hz，2H)，4.52-4.58(m，1H)，4.32-4.49(m，2H)，4.16(m，1H)，3.35(s，3H)，2.99-3.12(m，2H)，2.95(s，3H)，1.82(m，2H)，1.58(d，J＝7.0Hz，3H)，1.30-1.45(m，4H)，0.91(t，J＝6.9Hz，3H)；
LC-MS：m/z?695.1[M+H] +；
[α] D 18＝-58.4°(c?0.55，MeOH)。
Embodiment 46:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(1-hydroxy-3-methyl) butyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800422
The synthetic technology route is with reference to described in the embodiment 10, with 5-methyl isophthalic acid-hexin-3-alcohol (25 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 81.2%.
1H?NMR(300MHz，CD 3OD)：δ8.13(m，1H)，8.00(m，1H)，7.90(m，2H)，7.42(m，2H)，7.20-7.30(m，4H)，7.15(m，1H)，7.06(m，2H)，5.23(m，1H)，4.82(m，1H)，4.52-4.58(m，1H)，4.33-4.46(m，2H)，4.16(m，1H)，3.35(s，3H)，2.99-3.12(m，2H)，2.95(s，3H)，1.62-1.78(m，3H)，1.58(d，J＝7.0Hz，3H)，0.95(t，J＝6.1Hz，6H)；
13C?NMR(100MHz，CDCl 3)：δ166.3，164.9，161.9(d，J＝245Hz，1C)，142.0，1388，137.4，135.8，135.3，129.2，128.7，128.0，126.8，124.3，122.5，115.5，115.3，70.6，64.6，54.3，53.9，49.2，45.9，37.9，37.8，35.7，24.4，23.0，21.9，21.7；
LC-MS：m/z?695.0[M+H] +；
[α] D 18＝-55.4°(c?0.50，MeOH)。
Embodiment 47:N-[(1S, 2R)-1-benzyl-2-hydroxyl-3-(4-(1-hydroxyethyl-1,2,3-triazoles base))]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800431
(2S, 3R)-1, (the N-tertiary butyloxycarbonyl is amino)-(6g 22.8mmol) is dissolved in the 120mL methyl alcohol 4-phenylpropyl alcohol alkane 2-epoxy-3-, in system, adds NH with epoxy compounds 4Cl (2.22g, 41.5mmol), NaN 3(3.72g, 57.2mmol).Be heated to reflux state, reaction is spent the night to no raw material residue.Reaction solution is concentrated into volume is about 60mL, in the process that stirs, in system, add entry, have a large amount of white solids to separate out to 250mL.Filter, infrared oven dry, white solid (2S, 3R)-1-benzyl-2-hydroxyl-3-azido-t-butyl carbamate 6.3g, yield: 90.1%.Fusing point: 130-132 ℃.
1H?NMR(300MHz，CDCl 3)：δ7.25(m，5H)，4.95(d，J＝9.0Hz，1H)，3.76(m，2H)，3.39(m，2H)，2.89(m，3H)，1.41(s，9H)；
LC-MS：m/z?306.6[M+H] +；
[α] D 19＝+7.2°(c?1.000，MeOH)。
With trinitride (2S, 3R)-(306mg 1mmol) is dissolved in the 4mL methylene dichloride 1-benzyl-2-hydroxyl-3-azido-t-butyl carbamate, in system, adds the 1mL trifluoroacetic acid, room temperature reaction 3h.Concentrate unprocessed next step reaction of direct entering of the amine that obtains.
With 5-(methyl methylsulfonyl) amino-3-((1R)-1-(4-fluorophenyl)) ethyl aminocarbonyl phenylformic acid (354mg 0.9mmol) is dissolved among the 2mL DMF, add EDCI (173mg, 0.9mmol), HOBt (122mg, 0.9mmol), stirring at room 10min.The amine that the last step was obtained is dissolved in the DMF of 2mL, and (258mg 2mmol), splashes into above-mentioned reaction system with it, then the following 70 ℃ of reaction 15min of microwave condition to add DIPEA.In system, add 30mL water, ethyl acetate extraction (30mL * 2) merges organic phase; Diluted Acid Washing (15mL * 2), saturated sodium bicarbonate is washed (15mL * 2), saturated common salt washing (20mL); Anhydrous sodium sulfate drying filters, and concentrates; Column chromatography obtain weak yellow foam shape solid N-[(1S, 2R)-1-benzyl-2-hydroxyl-3-azido-]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine 614mg, yield: 52.7%.Fusing point: 68-70 ℃.
1H?NMR(300MHz，CDCl 3)：δ8.04(s，1H)，7.93(t，J＝1.8Hz，1H)，7.84(t，J＝1.8Hz，1H)，7.32(m，2H)，7.24(m，4H)，7.00(m，4H)，5.25(m，1H)，4.33(m，1H)，3.84(m，1H)，3.50(m，1H)，3.35(d，J＝6.0Hz，2H)，3.31(s，3H)，3.00(d，J＝4.8Hz，1H)，2.85(s，3H)，1.56(d，J＝6.9Hz，3H)；
13C?NMR(100MHz，CDCl 3)：δ165.9，164.8，161.9(d，J＝245Hz，1C)，142.1，138.5，137.3，135.6，135.4，129.2，128.7，127.9，127.8，127.7，127.6，126.8，124.1，70.4，54.8，53.6，49.2，37.9，37.8，35.5，21.6；
LC-MS：m/z?583.0[M+H] +；
[α] D 18＝-46.3°(c?0.600，MeOH).
The synthesis step of triazole compounds is with embodiment 10; With N-[(1S, 2R)-1-benzyl-2-hydroxyl-3-azido-]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine (29mg, 0.05mmol) replacement N-[(1S; 2S)-1-benzyl-2-hydroxyl-3-azido-]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine; 3-butyne-2-alcohol (16 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 74.2%.
1H?NMR(300MHz，CD 3OD)：δ8.04(m，1H)，7.96(m，1H)，7.90(s，1H)，7.79(m，1H)，7.42(m，2H)，7.19-7.28(m，4H)，7.15(m，1H)，7.06(m，2H)，5.22(m，1H)，4.97(m，1H)，4.63-4.69(m，1H)，4.26-4.42(m，2H)，4.07(m，1H)，3.33(s，3H)，3.27(m，1H)，2.93(s，3H)，2.85(m，1H)，1.56(d，J＝7.1Hz，3H)，1.52(q，J＝2.0，16.6Hz，3H)；
13C?NMR(100MHz，CDCl 3)：δ166.6，165.1，161.8(d，J＝245Hz，1C)，141.9，138.9，137.5，137.4，135.9，135.1，129.2，128.7，128.0，127.9，126.8，124.2，122.7，115.4，115.2，72.1，62.4，54.6，53.2，49.1，37.8，35.8，35.7，22.8，21.6；
LC-MS：m/z?653.1[M+H] +；
[α] D 17＝-54.9°(c?0.45，MeOH)。
Embodiment 48:N-[(1S, 2R)-1-benzyl-2-hydroxyl-3-(4-(1-hydroxyl-1-methyl) ethyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800451
The synthetic technology route is with reference to described in the embodiment 47, with 2-methyl-3-butyne-2-alcohol (20 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 80.6%.
1H?NMR(300MHz，CD 3OD)：δ8.03(m，1H)，7.96(m，1H)，7.86(s，1H)，7.80(m，1H)，7.42(m，2H)，7.19-7.29(m，4H)，7.15(m，1H)，7.06(m，2H)，5.22(m，1H)，4.62-4.68(m，1H)，4.26-4.41(m，2H)，4.07(m，1H)，3.34(s，3H)，3.27(m，1H)，2.94(s，3H)，2.86(m，1H)，1.56(m，9H)；
LC-MS：m/z?667.0[M+H] +；
[α] D 17＝-26.0°(c?0.20，MeOH)。
Embodiment 49:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-((1S)-1-hydroxyethyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800452
The synthetic technology route is with reference to described in the embodiment 10, with (R)-2-methyl-3-butyne-2-alcohol (16 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 62.7%.
1H?NMR(300MHz，CD 3OD)：δ8.92(d，J＝7.4Hz，1H)，8.35(d，J＝8.9Hz，1H)，8.12(m，1H)，7.99(m，1H)，7.89(m，2H)，7.43(m，2H)，7.21-7.30(m，4H)，7.16(m，1H)，7.04(m，2H)，5.24(m，1H)，4.96(m，1H)，4.51-4.57(m，1H)，4.46(m，2H)，4.32-4.40(m，1H)，4.17(m，1H)，3.35(s，3H)，2.97-3.12(m，2H)，2.96(s，3H)，1.58(d，J＝7.0Hz，3H)，1.50(d，J＝6.6Hz，3H)；
LC-MS：m/z?653.1[M+H] +；
HRMS：calcd?for?C 32H 37FN 6O 6SNa?675.2377，found?C 32H 37FN 6O 6SNa?675.2390；
[α] D 23＝-36°(c?0.20，MeOH)。
Embodiment 50:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-((1S)-1-hydroxyethyl-1,2,3-triazoles base))]-5-[(methyl first sulfo group) amino]-N '-[(1S)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800461
The synthetic technology route is with reference to described in the embodiment 10, with (S)-2-methyl-3-butyne-2-alcohol (16 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 70.3%.
1H?NMR(300MHz，CD 3OD)：δ8.91(d，J＝7.8Hz，1H)，8.36(d，J＝9.5Hz，1H)，8.12(m，1H)，7.99(m，1H)，7.89(m，2H)，7.43(m，2H)，7.21-7.30(m，4H)，7.16(m，1H)，7.04(m，2H)，5.24(m，1H)，4.94(m，1H)，4.52-4.57(m，1H)，4.46(m，2H)，4.32-4.40(m，1H)，4.17(m，1H)，3.35(s，3H)，2.97-3.12(m，2H)，2.96(s，3H)，1.58(d，J＝7.0Hz，3H)，1.51(d，J＝6.6Hz，3H)；
LC-MS：m/z?653.0[M+H] +；
HRMS：calcd?for?C 32H 37FN 6O 6SNa?675.2377，found?C 32H 37FN 6O 6SNa?675.2366。
Embodiment 51:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-methylol-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine
Figure BSA00000394448800462
According to synthetic route 1, and the trinitride that will make with reference to embodiment 1 (2S, 3S)-1-benzyl-2-hydroxyl-3-azido-t-butyl carbamate (306mg; 1mmol) and propynol (118 μ L 2mmol) join in the water of THF and 1mL of 4mL, after stirring; Add 0.1 normal anti-sepsis acid sodium (20mg; 0.1mmol), 0.05 normal cupric sulfate pentahydrate (13mg, 0.05mmol).Be reflected at counter spending the night under the condition of 50 ℃ of heating.Concentrate, add water (10mL), ethyl acetate extraction (10mL * 3) merges organic phase, and with saturated common salt washing (10mL * 1), anhydrous sodium sulfate drying filters, concentrate crude product 320mg, not purifiedly directly carry out next step reaction;
(36mg 0.1mmol) is dissolved in the methylene dichloride of 1mL the crude product that the last step was obtained, and adds the trifluoroacetic acid of 0.2mL, under room temperature, stirs 2h.The unhindered amina that obtains after concentrating sloughing behind the Boc directly carries out next step reaction;
(34mg 0.09mmol) is dissolved in the 1mL dry DMF, the ice-water bath cooling to get (R)-3-(N-methyl methylsulfonyl) amino-5-N-(1-phenyl) ethyl carbamyl phenylformic acid; Add successively EDCI (18mg, 0.9mmol), HOBt (12mg; 0.09mmol), DIPEA (76 μ L, 0.44mmol); After stirring 5min, add the above-mentioned amine that is dissolved in 1mL DMF, let reaction system heat up naturally and react 10min down for 70 ℃ in microwave-assisted.Add 30mL ETHYLE ACETATE, organic layer is washed (10mL * 2) twice with saturated sodium bicarbonate, washes one time (10mL * 1); Saturated common salt water washing one time (10mL * 1), anhydrous sodium sulfate drying filters; Concentrate, directly the TLC chromatography gets end product 206.36mg, yield: 58.1%.
1H?NMR(300MHz，CD 3OD)：δ8.12(m，1H)，7.99(m，1H)，7.93(s，1H)，7.88(m，1H)，7.42(m，2H)，7.20-7.35(m，7H)，7.12-7.17(m，1H)，7.06(m，2H)，5.24(m，1H)，4.65(s，2H)，4.53-4.59(m，1H)，4.34-4.48(m，2H)，4.16(m，1H)，3.35(s，3H)，2.99-3.12(m，2H)，2.95(s，3H)，1.58(d，J＝7.1Hz，3H)；
LC-MS：m/z?621.1[M+H] +；
[α] D 18＝-58.2°(c?0.45，MeOH)。
Embodiment 52:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-methylol-1,2,3-triazoles base)]-5-nitro-N ', N '-[dipropyl] isophthaloyl amine
Figure BSA00000394448800471
The synthetic technology route is with reference to described in the embodiment 51; Just with 3-nitro-5-(N; The N-dipropyl) carbamyl phenylformic acid (26mg, 0.09mmol) replacement (R)-3-(N-methyl methylsulfonyl) amino-5-N-(1-phenyl) ethyl carbamyl phenylformic acid, yield: 59.6%.
1H?NMR(300MHz，CD 3OD)：δ8.62(m，1H)，8.32(m，1H)，8.04(m，1H)，7.95(s，1H)，7.20-7.31(m，4H)，7.15(m，1H)，4.66(s，2H)，4.55-4.61(m，1H)，4.36-4.52(m，2H)，4.19(m，1H)，3.50(t，J＝7.9Hz，2H)，3.190(t，J＝7.4Hz，2H)，2.98-3.15(m，2H)，1.75(m，2H)，1.57(m，2H)，1.02(t，J＝7.5Hz，3H)，0.75(t，J＝7.2Hz，3H)；
LC-MS：m/z?539.2[M+H] +；
[α] D 18＝-67.0°(c?0.80，MeOH)。
Embodiment 53:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-methylol-1,2,3-triazoles base)]-5-methyl-N ', N '-[dipropyl] isophthaloyl amine
Figure BSA00000394448800481
The synthetic technology route is with reference to described in the embodiment 51; Just with 5-methyl-3-(N; The N-dipropyl) carbamyl phenylformic acid (24mg, 0.09mmol) replacement (R)-3-(N-methyl methylsulfonyl) amino-5-N-(1-phenylethyl) carbamyl phenylformic acid, yield: 59.6%.
1H?NMR(300MHz，CD 3OD)：δ7.93(s，1H)，7.64(s，1H)，7.47(s，1H)，7.13-7.31(m，6H)，4.66(s，2H)，4.53-4.59(m，1H)，4.46(m，1H)，4.31-4.39(m，1H)，4.16(m，1H)，3.47(t，J＝7.2Hz，2H)，3.18(t，J＝7.3Hz，2H)，2.96-3，12(m，2H)，2.43(s，3H)，1.72(q，J＝7.5，14.8Hz，2H)，1.54(q，J＝7.8，14.8Hz，2H)，1.00(t，J＝7.3Hz，3H)，0.72(t，J＝7.3Hz，3H)；
LC-MS：m/z?508.2[M+H] +；
[α] D 18＝-50.0°(c?0.85，MeOH)。
Embodiment 54:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-methylol-1,2,3-triazoles base)]-5-methyl-N '-[(R)-and 2-(methoxymethyl) pyrroles] isophthaloyl amine
Figure BSA00000394448800482
The synthetic technology route is with reference to described in the embodiment 51; Just with 5-methyl-3-((R)-2-(methoxymethyl) pyrroles) formyl radical phenylformic acid (25mg; 0.09mmol) replacement (R)-3-(N-methyl methylsulfonyl) amino-5-N-(1-phenyl) ethyl carbamyl phenylformic acid, yield: 64.2%.
1H?NMR(300MHz，CD 3OD)：δ7.93(s，1H)，7.65(s，1H)，7.61(s，1H)，7.45(s，1H)，7.13-7.31(m，5H)，4.66(s，2H)，4.53-4.59(m，1H)，4.45(m，1H)，4.32-4.40(m，2H)，4.16(m，1H)，3.63(d，J＝4.7Hz，2H)，3.34-3.51(m，4H)，2.96-3，14(m，3H)，2.43(s，3H)，1.90-2.15(m，3H)，1.72-1.83(m，1H)；
LC-MS：m/z?522.2[M+H] +；
[α] D 18＝-115.3°(c?0.45，MeOH)。
Embodiment 55:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-methylol-1,2,3-triazoles base)]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine
Figure BSA00000394448800491
The synthetic technology route is with reference to described in the embodiment 51; Just with (R)-3-N-(1-(4-fluorophenyl) ethyl) carbamyl phenylformic acid (26mg; 0.09mmol) replacement (R)-3-(N-methyl methylsulfonyl) amino-5-N-(1-phenyl) ethyl carbamyl phenylformic acid, yield: 71.3%.
1H?NMR(300MHz，CD 3OD)：δ8.19(m，1H)，7.97(m，1H)，7.92(s，1H)，7.87(m，1H)，7.53(m，1H)，7.43(m，2H)，7.21-7.31(m，4H)，7.14(m，1H)，7.10(m，2H)，5.24(m，1H)，4.65(s，2H)，4.52-4.58(m，1H)，4.47(m，1H)，4.26-4.40(m，1H)，4.16(m，1H)，2.96-3.12(m，2H)，1.57(d，J＝7.0Hz，3H)；
LC-MS：m/z?532.1[M+H] +；
[α] D 17＝-51.2°(c?0.75，MeOH).
Embodiment 56:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-propyl group-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine
Figure BSA00000394448800492
Triazo-compound N-[(1S; 2S)-1-benzyl-2-hydroxyl-3-azido-]-compound method of 5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine and embodiment 1 in compound N-[(1S; 2S)-1-benzyl-2-hydroxyl-3-azido-]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine compound method is identical; Just with 5-(methyl methylsulfonyl) amino-3-((1R)-1-phenyl) ethyl aminocarbonyl phenylformic acid replacement 5-(methyl methylsulfonyl) amino-3-((1R)-1-(4-fluorophenyl) ethyl) aminocarbonyl phenylformic acid; Get white foam shape solid, yield: 74.2%.
1H?NMR(300MHz，CD 3OD)：δ8.09(m，1H)，7.98(m，1H)，7.85(m，1H)，7.20-7.41(m，10H)，5.48(m，1H)，4.40(m，1H)，3.86(m，1H)，3.33(m，5H)，2.93-3.12(m，2H)，2.93(s，3H)，1.57(d，J＝7.2Hz，3H)；
LC-MS：m/z?565.1[M+H] +.
Operating process is with embodiment 10; Just with compound N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-azido-]-(28mg 0.05mmol) replaces compound N-[(1S to isophthaloyl amine to 5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl]; 2S)-1-benzyl-2-hydroxyl-3-azido-]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and 1-(4-fluorophenyl) ethyl] isophthaloyl amine; With 1-pentyne (20 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 73.5%.
1H?NMR(300MHz，CD 3OD)：δ8.33(d，J＝9.5Hz，1H)，8.12(m，1H)，7.99(m，1H)，7.88(m，1H)，7.78(s，1H)，7.40(m，2H)，7.20-7.36(m，7H)，7.16(m，1H)，7.06(m，2H)，5.24(m，1H)，4.50-4.56(m，1H)，4.31-4.47(m，2H)，4.14(m，1H)，3.35(s，3H)，2.99-3.12(m，2H)，2.95(s，3H)，2.64(t，J＝7.5Hz，2H)，1.60-1.72(m，2H)，1.58(d，J＝7.2Hz，3H)，0.95(t，J＝7.5Hz，3H)；
LC-MS：m/z?633.2[M+H] +；
[α] D 17＝-48.0°(c?0.20，MeOH)。
Embodiment 57:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-butyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine
Figure BSA00000394448800501
The synthetic technology route is with reference to described in the embodiment 56, with 1-hexin (23 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 69.8%.
1H?NMR(300MHz，CD 3OD)：δ8.13(m，1H)，8.00(m，1H)，7.89(m，1H)，7.74(s，1H)，7.14-7.42(m，10H)，5.24(m，1H)，4.40-4.54(m，2H)，4.30-4.38(m，1H)，4.14(m，1H)，3.34(s，3H)，2.98-3.10(m，2H)，2.95(s，3H)，2.66(t，J＝7.2Hz，2H)，1.57-1.67(m，5H)，1.33-1.43(m，2H)，0.94(t，J＝7.4Hz，3H)；
LC-MS：m/z?647.2[M+H] +；
HRMS：calcd?for?C 34H 42N 6O 5SNa?669.2835，found?C 34H 42N 6O 5SNa?669.2793；
[α] D 17＝-61.3°(c?0.55，MeOH)。
Embodiment 58:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-amyl group-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine
Figure BSA00000394448800502
The synthetic technology route is with reference to described in the embodiment 56, with (26 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 79.5%.
1H?NMR(300MHz，CD 3OD)：δ8.90(d，J＝8.0Hz，1H)，8.33(d，J＝9.3Hz，1H)，8.12(m，1H)，7.99(m，1H)，7.88(m，1H)，7.74(s，1H)，7.42(m，2H)，7.20-7.39(m，7H)，7.16(m，1H)，5.24(m，1H)，4.48-4.54(m，1H)，4.30-4.47(m，2H)，4.14(m，1H)，3.34(s，3H)，2.99-3.12(m，2H)，2.95(s，3H)，2.65(t，J＝7.5Hz，2H)，1.52-1.69(m，5H)，1.32(m，4H)，0.91(m，3H)；
13C?NMR(100MHz，CDCl 3)：δ166.2，164.8，148.2，142.8，142.2，137.4，135.9，135.4，129.3，128.7，128.6，127.8，127.7，127.5，126.7，126.3，123.9，122.4，70.4，54.2，49.8，37.9，37.8，35.7，31.3，29.7，25.1，22.2，21.7，13.7；
LC-MS：m/z?661.1[M+H] +；
[α] D 17＝-37.0°(c?0.10，MeOH)。
Embodiment 59:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-sec.-propyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine
Figure BSA00000394448800511
The synthetic technology route is with reference to described in the embodiment 56, with 3-methyl isophthalic acid-butine (19 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 78.9%.
1H?NMR(300MHz，CD 3OD)：δ8.12(m，1H)，7.99(m，1H)，7.89(m，1H)，7.74(s，1H)，7.42(m，2H)，7.20-7.36(m，7H)，7.16(m，1H)，5.24(m，1H)，4.48-4.56(m，1H)，4.42-4.47(m，1H)，4.30-4.37(m，1H)，4.14(m，1H)，3.35(s，3H)，2.99-3.12(m，3H)，2.96(s，3H)，1.59(d，J＝7.3Hz，3H)，1.27(d，J＝6.8Hz，6H)；
LC-MS：m/z633.2[M+H] +；
[α] D 17＝-32.9°(c?0.55，MeOH)。
Embodiment 60:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-cyclopropyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine
Figure BSA00000394448800512
The synthetic technology route is with reference to described in the embodiment 56, yield: 80.3%.
1H?NMR(300MHz，CD 3OD)：δ8.11(m，1H)，7.99(m，1H)，7.88(m，1H)，7.69(s，1H)，7.42(m，2H)，7.24-7.36(m，7H)，7.16(m，1H)，5.24(m，1H)，4.46-4.52(m，1H)，4.41-4.45(m，1H)，4.27-4.35(m，1H)，4.13(m，1H)，3.35(s，3H)，2.99-3.12(m，2H)，2.95(s，3H)，1.88-1.97(m，1H)，1.58(d，J＝7.1Hz，3H)，0.91-0.97(m，1H)，0.71-0.76(m，1H)；
13C?NMR(100MHz，CDCl 3)：δ166.3，164.8，149.9，142.9，142.1，137.4，135.9，135.3，129.3，128.7，128.6，127.9，127.8，127.5，126.7，124.0，121.5，70.4，54.3，54.1，49.8，37.9，37.7，35.6，21.7，7.7，6.4；
LC-MS：m/z?631.2[M+H] +；
[α] D 17＝-45.6°(c?0.80，MeOH)。
Embodiment 61:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(the 4-tertiary butyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine
Figure BSA00000394448800521
The synthetic technology route is with reference to described in the embodiment 56, with tertiary butyl acetylene (25 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 81.7%.
1H?NMR(300MHz，CD 3OD)：δ8.15(m，1H)，8.00(m，1H)，7.91(m，1H)，7.75(s，1H)，7.42(m，2H)，7.20-7.36(m，7H)，7.16(m，1H)，5.24(m，1H)，4.48-4.56(m，1H)，4.42-4.46(m，1H)，4.30-4.38(m，1H)，4.13(m，1H)，3.35(s，3H)，2.99-3.12(m，2H)，2.95(s，3H)，1.59(d，J＝7.1Hz，3H)，1.31(s，9H)；
LC-MS：m/z?647.0[M+H] +；
[α] D 17＝-55.1°(c?0.45，MeOH)。
Embodiment 62:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(2-methyl) propyl group-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine
Figure BSA00000394448800531
The synthetic technology route is with reference to described in the embodiment 56, with 4-methyl-1-pentene alkynes (23 μ l, 0.2mmol) replacement cyclopropyl acethlene, yield: 67.8%.
1H?NMR(300MHz，CD 3OD)：δ8.12(m，1H)，8.00(m，1H)，7.89(m，1H)，7.75(s，1H)，7.42(m，2H)，7.20-7.36(m，7H)，7.16(m，1H)，5.24(m，1H)，4.47-4.55(m，1H)，4.41-4.49(m，1H)，4.31-4.41(m，1H)，4.14(m，1H)，3.36(s，3H)，2.99-3.12(m，2H)，2.95(s，3H)，2.54(d，J＝6.9Hz，2H)，1.86-1.96(m，1H)，1.59(d，J＝7.0Hz，3H)，0.93(d，J＝6.8Hz，6H)；
LC-MS：m/z?647.2[M+H] +；
HRMS：calcd?for?C 34H 42N 6O 5SNa?669.2835，found?C 34H 42N 6O 5SNa?669.2852；
[α] D 17＝-44.0°(c?0.25，MeOH)。
Embodiment 63:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(1-methyl) butyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine
Figure BSA00000394448800532
The synthetic technology route is with reference to described in the embodiment 56, with 3-methyl isophthalic acid-hexin (28 μ l, 0.2mmol) replacement cyclopropyl acethlene, yield: 83.5%.
1H?NMR(300MHz，CD 3OD)：δ8.16(m，1H)，8.01(m，1H)，7.91(m，1H)，7.75(s，1H)，7.42(m，2H)，7.20-7.36(m，7H)，7.16(m，1H)，5.24(m，1H)，4.49-4.55(m，1H)，4.43-4.47(m，1H)，4.31-4.39(m，1H)，4.14(m，1H)，3.35(s，3H)，2.99-3.12(m，2H)，2.95(s，3H)，2.84-2.93(m，1H)，1.48-1.71(m，6H)，1.22-1.36(m，4H)，0.90(t，J＝7.3Hz，3H)；
LC-MS：m/z?661.1[M+H] +；
[α] D 17＝-51.8°(c?0.60，MeOH)。
Embodiment 64:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-cyclopentyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine
The synthetic technology route is with reference to described in the embodiment 56, with cyclopentyl acetylene (23 μ l, 0.2mmol) replacement cyclopropyl acethlene, yield: 86.2%.
1H?NMR(300MHz，CD 3OD)：δ8.12(m，1H)，8.00(m，1H)，7.0(m，1H)，7.74(s，1H)，7.41(m，2H)，7.20-7.36(m，7H)，7.16(m，1H)，5.24(m，1H)，4.41-4.53(m，2H)，4.29-4.37(m，1H)，4.14(m，1H)，3.35(s，3H)，2.98-3.14(m，2H)，2.95(s，3H)，2.04(m，2H)，1.57-1.80(m，9H)；
LC-MS：m/z?659.0[M+H] +；
HRMS：calcd?for?C 35H 42N 6O 5SNa?681.2835，found?C 35H 42N 6O 5SNa?681.2830；
[α] D 17＝-37.0°(c?0.10，MeOH)。
Embodiment 65:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(3-methyl) butyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine
Figure BSA00000394448800542
The synthetic technology route is with reference to described in the embodiment 56, with 5-methyl isophthalic acid-hexin (25 μ l, 0.2mmol) replacement cyclopropyl acethlene, yield: 86.4%.
1H?NMR(300MHz，CD 3OD)：δ8.13(m，1H)，8.00(m，1H)，7.89(s，1H)，7.73(m，1H)，7.14-7.42(m，9H)，5.24(m，1H)，4.47-4.54(m，1H)，4.44(m，1H)，4.30-4.37(m，1H)，3.34(s，3H)，2.97-3.12(m，2H)，2.94(s，3H)，2.66(t，J＝7.7Hz，2H)，1.49-1.59(m，5H)，0.93(d，J＝6.1Hz，9H)；
LC-MS：m/z?661.2[M+H] +；
[α] D 23＝-49.7°(c?0.90，MeOH)。
Embodiment 66:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-phenyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine
Figure BSA00000394448800551
The synthetic technology route is with reference to described in the embodiment 56, with phenylacetylene (22 μ l, 0.2mmol) replacement cyclopropyl acethlene, yield: 93.6%.
1H?NMR(300MHz，CD 3OD)：δ8.29(s，1H)，8.13(m，1H)，7.98(m，1H)，7.88(m，1H)，7.76(m，1H)，7.74(s，1H)，7.20-7.42(m，12H)，7.14(m，1H)，5.24(m，1H)，4.57-4.63(m，1H)，4.39-4.57(m，2H)，4.21(m，1H)，3.31(s，3H)，2.97-3.13(m，2H)，2.92(s，3H)，1.57(d，J＝7.1Hz，3H)；
LC-MS：m/z?667.2[M+H] +；
[α] D 17＝-125.3°(c?0.40，MeOH)。
Embodiment 67:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(the 4-tertiary butyl) phenyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine
Figure BSA00000394448800552
The synthetic technology route is with reference to described in the embodiment 56, with 4-tert.-butylbenzene acetylene (34 μ l, 0.2mmol) replacement cyclopropyl acethlene, yield: 92.1%.
1H?NMR(300MHz，CD 3OD)：δ8.25(s，1H)，8.14(m，1H)，7.98(m，1H)，7.88(m，1H)，7.69(m，1H)，7.66(s，1H)，7.42(m，4H)，7.20-7.35(m，7H)，7.16(m，1H)，5.24(m，1H)，4.57-4.63(m，1H)，4.39-4.56(m，2H)，4.21(m，1H)，3.34(s，3H)，2.97-3.13(m，2H)，2.93(s，3H)，1.58(d，J＝7.0Hz，3H)，1.33(s，9H)；
LC-MS：m/z?723.3[M+H] +；
[α] D 17＝-73.4°(c?0.35，MeOH)。
Embodiment 68:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-((1R)-1-hydroxyl) ethyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine
Figure BSA00000394448800561
The synthetic technology route is with reference to described in the embodiment 56, with (R)-(+)-3-butyne-2-alcohol (16 μ l, 0.2mmol) replacement cyclopropyl acethlene, yield: 62.3%.
1H?NMR(300MHz，CD 3OD)：δ8.92(d，J＝7.5Hz，1H)，8.37(d，J＝9.2Hz，1H)，8.15(m，1H)，8.00(m，1H)，7.89(m，2H)，7.21-7.43(m，10H)，5.25(m，1H)，4.94(m，1H)，4.52-4.58(m，1H)，4.33-4.51(m，2H)，4.17(m，1H)，3.35(s，3H)，2.87-3.13(m，5H)，1.59(d，J＝7.1Hz，3H)，1.51(d，J＝6.3Hz，3H)；
LC-MS：m/z635.1[M+H] +。
[α] D 23＝-36°(c?0.20，MeOH)。
Embodiment 69:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-((1S)-1-hydroxyl) ethyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine
Figure BSA00000394448800562
The synthetic technology route is with reference to described in the embodiment 56, with (S)-(+)-3-butyne-2-alcohol (16 μ L, 0.2mmol) replacement cyclopropyl acethlene, yield: 52.1%.
1H?NMR(300MHz，CD 3OD)：δ8.91(d，J＝8.1Hz，1H)，8.37(d，J＝9.2Hz，1H)，8.13(m，1H)，8.00(m，1H)，7.89(m，2H)，7.12-7.42(m，10H)，5.25(m，1H)，4.95(m，1H)，4.52-4.58(m，1H)，4.33-4.51(m，2H)，4.16(m，1H)，3.35(s，3H)，2.87-3.13(m，5H)，1.59(d，J＝7.0Hz，3H)，1.51(q，J＝2.9，6.8Hz，3H)；
LC-MS：m/z?635.1[M+H] +；
[α] D 23＝-76.5°(c?0.40，MeOH)。
Embodiment 70:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(1-hydroxyl) butyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine
The synthetic technology route is with reference to described in the embodiment 56, with 1-hexin-3-alcohol (23 μ l, 0.2mmol) replacement cyclopropyl acethlene, yield: 78.8%.
1H?NMR(300MHz，CD 3OD)：δ8.90(d，J＝7.5Hz，1H)，8.34(d，J＝9.1Hz，1H)，8.12(m，1H)，7.99(m，1H)，7.88(m，2H)，7.42(m，2H)，7.20-4.37(m，7H)，7.15(m，1H)，5.25(m，1H)，4.77(d，J＝6.7Hz，1H)，4.51-4.57(m，1H)，4.32-4.47(m，2H)，4.17(m，1H)，3.35(s，3H)，2.97-3.10(m，2H)，2.95(s，3H)，1.79(q，J＝7.6，13.6Hz，2H)，1.58(d，J＝7.1Hz，3H)，1.32-1.52(m，2H)，0.95(t，J＝7.3Hz，3H)；
LC-MS：m/z?665.3[M+H] +
[α] D 17＝-66°(c?0.35，MeOH)。
Embodiment 71:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(1-hydroxy-2-methyl) propyl group-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine
The synthetic technology route is with reference to described in the embodiment 10, with 4-methyl-1-pentene alkynes-3-alcohol (21 μ l, 0.2mmol) replacement cyclopropyl acethlene, yield: 71.5%.
1H?NMR(300MHz，CD 3OD)：δ8.12(m，1H)，7.99(m，1H)，7.89(m，1H)，7.86(s，1H)，7.42(m，2H)，7.20-4.37(m，7H)，7.15(m，1H)，5.24(m，1H)，4.51-4.57(m，2H)，4.32-4.47(m，2H)，4.17(m，1H)，3.35(s，3H)，2.97-3.10(m，2H)，2.95(s，3H)，2.00-2.11(m，1H)，1.58(d，J＝7.0Hz，3H)，0.95(d，J＝6.8Hz，3H)，0.87(d，J＝6.7Hz，3H)；
13C?NMR(100MHz，CDCl 3)：δ166.4，165.0，147.2，142.9，142.1，137.4，135.9，135.4，129.3，128.7，128.6，127.9，126.8，126.3，124.2，122.9，71.9，70.6，54.3，53.9，49.8，37.9，37.8，34.0，21.7，18.5，17.8；
LC-MS：m/z?663.0[M+H] +；
[α] D 17＝-51.6°(c?0.35，MeOH)。
Embodiment 72:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(1-hydroxyl) amyl group-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine
Figure BSA00000394448800581
The synthetic technology route is with reference to described in the embodiment 10, with 1-octyne-3-alcohol (29 μ l, 0.2mmol) replacement cyclopropyl acethlene, yield: 82.1%.
1H?NMR(300MHz，CD 3OD)：δ8.90(d，J＝7.7Hz，1H)，8.34(d，J＝9.2Hz，1H)，8.12(m，1H)，7.99(m，1H)，7.88(m，2H)，7.42(m，2H)，7.20-4.37(m，7H)，7.15(m，1H)，5.25(m，1H)，4.75(m，1H)，4.33-4.57(m，3H)，4.16(m，1H)，3.35(s，3H)，2.86-3.12(m，2H)，2.95(s，3H)，1.82(m，2H)，1.59(d，J＝7.1Hz，3H)，1.28-1.44(m，4H)，0.91(t，J＝6.9Hz，3H)；
LC-MS：m/z?677.1[M+H] +；
[α] D 17＝-66.3°(c?0.35，MeOH)。
Embodiment 73:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(1-hydroxy-3-methyl) butyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine
Figure BSA00000394448800582
The synthetic technology route is with reference to described in the embodiment 10, with 5-methyl isophthalic acid-hexin-3-alcohol (25 μ l, 0.2mmol) replacement cyclopropyl acethlene, yield: 83.2%.
1H?NMR(300MHz，CD 3OD)：δ8.13(m，1H)，8.00(m，1H)，7.9(m，2H)，7.12-7.42(m，10H)，5.24(m，1H)，4.85(m，1H)，4.51-4.57(m，1H)，4.32-4.47(m，2H)，4.16(m，1H)，3.34(s，3H)，2.98-3.12(m，2H)，2.95(s，3H)，1.62-1.80(m，3H)，1.59(d，J＝7.1Hz，3H)，0.95(d，J＝6.3Hz，3H)；
13C?NMR(100MHz，CDCl 3)：δ166.3，165.0，151.4，142.9，142.0，137.5，135.9，135.4，129.3，128.7，128.6，127.9，127.5，126.7，124.3，122.5，70.6，64.7，54.3，53.9，49.8，45.9，37.9，37.7，35.7，24.4，23.0，21.9，21.6；
LC-MS：m/z?677.0[M+H] +；
[α] D 17＝-62.0°(c?0.75，MeOH)。
Embodiment 74:N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-(4-(1-hydroxyl-2-(3-trifluoromethyl) phenoxy) ethyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine
The synthetic technology route is with reference to described in the embodiment 10, with 1-(3-trifluoromethyl) phenoxy-3-butyne-2-alcohol (23mg, 0.1mmol) replacement cyclopropyl acethlene, yield: 88.2%.
1H?NMR(300MHz，CD 3OD)：δ8.13(m，1H)，8.04(m，1H)，7.99(m，1H)，7.89(s，1H)，7.20-7.48(m，13H)，7.15(m，1H)，5.17-5.27(m，2H)，4.54-4.60(m，1H)，4.15-4.49(m，5H)，3.34(s，3H)，2.86-3.12(m，2H)，2.94(s，3H)，1.58(d，J＝7.1Hz，3H)；
LC-MS：m/z?795.0[M+H] +；
[α] D 17＝-51.6°(c?0.65，MeOH)。
Embodiment 75:N-[(1S, 2S)-1-benzyl-2-amino-3-(4-sec.-propyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine
Figure BSA00000394448800601
With trinitride H ((2S, 3R)-2-benzyl-4-azido--3-hydroxyl-1-tertbutyloxycarbonyl propylamine) (and 3.06g, 10mmol), phthalic imidine (1.59g; 12mmol), (4.71g 20mmol) is dissolved among the 60mL exsiccant THF triphenylphosphine, under protection of nitrogen gas, in system, adds azoformic acid isopropyl ester (3.6g; 20mmol), room temperature reaction 6h concentrates; Directly carry out column chromatography, obtain the solid I 4.03g of white, yield: 92.6%.
1H?NMR(300MHz，CDCl3)：δ7.90(m，2H)，7.78(m，2H)，7.22(m，5H)，5.80(d，J＝9.3Hz，1H)，4.51(m，1H)，3.96(m，1H)，3.69(m，1H)，2.72(m，2H)，1.33(s，9H)；
13C?NMR(100MHz，CD 3OD)：δ168.8，155.4，136.6，134.5，131.4，129.1，128.4，126.6，123.7，53.1，51.9，50.1，39.0，28.2；
LC-MS：m/z?379.8[M+H- tBu] +；
[α] D 18＝-70.2°(c?0.50，MeOH)。
Compound I ((2S, 3R)-2-benzyl-3-phthalimidyl-4-azido--1-tertbutyloxycarbonyl propylamine) (435mg 1.0mmol) adds in the methylene dichloride of 5mL, in system, adds the 1mL trifluoroacetic acid, under room temperature, reacts 2h.Concentrate, J ((2S, 3R)-2-benzyl-3-phthalimidyl-4-azido--1-propylamine) crude product, not purified next step reaction of direct entering.
(413mg 1.1mmol) is dissolved in the 4mL dry DMF, the ice-water bath cooling to get 5-(methyl methylsulfonyl) amino-3-((1R)-1-phenyl) ethyl aminocarbonyl phenylformic acid; Add successively EDCI (210mg, 1.1mmol), HOBt (149mg; 1.1mmol), DIPEA (760 μ L, 4.4mmol); After stirring 5min, add the J that is dissolved in 1mL DMF, let reaction system heat up naturally and react 10min down for 70 ℃ in microwave-assisted.Add 30mL ETHYLE ACETATE, organic layer is washed (10mL * 2) twice with saturated sodium bicarbonate, wash one time (10mL * 1), and saturated common salt water washing one time (10mL * 1), anhydrous sodium sulfate drying filters, concentrated crude product.Petrol ether/ethyl acetate=1/1-1/2 crosses post, white foam shape solid K (N-[(1S, 2S)-1-benzyl-2-amino-3-azido-]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-phenylethyl] isophthaloyl amine) 575mg, yield: 79.9%.Fusing point: 105-107 ℃.
1H?NMR(400MHz，CD 3OD)：δ7.90-7.99(m，1H)，7.81-7.86(m，3H)，7.77-7.81(m，2H)，7.64(m，1H)，7.38-7.41(m，2H)，7.30-7.35(m，2H)，7.18-7.27(m，5H)，7.10-7.14(m，1H)，5.20(q，J＝7.0，14.0Hz，1H)，4.89-4.95(m，1H)，4.60-4.66(m，1H)，4.26(q，J＝2.6，3.2Hz，1H)，3.93(q，J＝5.4，12.5Hz，1H)，3.29(s，3H)，3.10(q，J＝4.5，14.0Hz，1H)，2.92(s，3H)，2.80(q，J＝2.8，3.5Hz，1H)，1.55(d，J＝7.0Hz，9H)；
13C?NMR(100MHz，CD 3OD)：δ169.2，165.0，164.5，142.8，142.4，136.3，136.0，135.2，134.8，131.2，129.1，128.7，128.5，127.9，127.5，127.2，126.9，126.2，124.0，123.7，52.7，51.6，50.1，49.6，38.8，37.9，35.5，21.0；
LC-MS：m/z?694.0[M+H] +；
[α] D 17＝-55.0°(c?0.70，MeOH)。
Triazo-compound K (N-[(1S, 2S)-1-benzyl-2-amino-3-azido-]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine) (35mg is 0.05mmol) with 3-methyl isophthalic acid-acetylene (19 μ L; 0.2mmol) join in the water of THF and 200 μ L of 800 μ L; After stirring, add 0.2 normal anti-sepsis acid sodium (2mg, 0.01mmol); 0.1 normal cupric sulfate pentahydrate (1mg, 0.005mmol).Be reflected under the condition of 50 ℃ of heating and react 12-24h, directly obtain the midbody triazole compounds through the TLC chromatography.The midbody that obtains is dissolved in the ethanol of 1mL, adds NH 2NH 2H 2(20uL 0.4mmol), reacts under the condition of 60 ℃ of heating and reacts 24h O.Reaction solution concentrates, and directly obtains end product L 9mg, yield: 28.6% through the TLC chromatography.
Figure BSA00000394448800611
1H?NMR(300MHz，CD 3OD)：δ8.11(t，J＝1.6Hz，1H)，7.99(t，J＝1.6Hz，1H)，7.87(t，J＝1.6Hz，1H)，7.78(s，1H)，7.11-7.42(m，10H)，5.24(q，J＝6.8，14.2Hz，1H)，4.52-4.59(m，1H)，4.32-4.45(m，2H)，3.50(m，1H)，3.34(s，3H)，2.92-3.13(m，6H)，1.59(d，J＝7.1Hz，3H)，1.30(d，J＝11.4Hz，3H)，1.27(d，J＝11.5Hz，3H)；
LC-MS：m/z?632.1[M+H] +。
Embodiment 76:N-[(1S, 2S)-1-benzyl-2-amino-3-(the 4-tertiary butyl-1,2,3-triazoles base)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-and the 1-phenylethyl] isophthaloyl amine
Figure BSA00000394448800621
The synthetic technology route is with reference to described in the embodiment 75, with tertiary butyl acetylene (16mg, 0.2mmol) replacement 3-methyl isophthalic acid-acetylene, yield: 23.1%.
1H?NMR(300MHz，CD3OD)：δ8.10(t，J＝1.5Hz，1H)，7.99(t，J＝1.6Hz，1H)，7.87(t，J＝1.5Hz，1H)，7.80(s，1H)，7.30-7.42(m，4H)，7.11-7.26(m，6H)，5.24(q，J＝7.1，14.0Hz，1H)，4.32-4.58(m，3H)，3.50(m，1H)，3.35(s，3H)，2.85-3.12(m，5H)，1.59(d，J＝7.0Hz，3H)，1.33(s，9H)；
LC-MS：m/z?646.1[M+H]+。
Experimental example: the determination of activity of hydroxyethyl triazole class compounds or aminoethyl triazole class compounds:
(1) the proteic acquisition of beta-secretase:
The beta-secretase extracellular region protein is adopted in experiment, and 1-454 amino acid (hereinafter referred BACE1) is secretory protein, and this is proteic gene constructed in pFastBac TMIn 1 carrier, the C end adds 6 Histidines.(Invitrogen) baculovirus expression system obtains target protein through .
At first recombinant plasmid transformed is arrived intestinal bacteria DH10Bac TMIn the competent cell, wherein comprised the baculovirus shuttle vectors, i.e. rod granule, picking contains pFastBac after transposition TMThe recombinant clone of middle goal gene section is cultivated and extracting reorganization rod granule.With the Sf9 insect cell of reorganization rod granule transfection complete TNM-FH culture medium culturing, cultivate and gather in the crops the substratum that contains first-generation virus after 3-5 days, continue transfection and obtain the s-generation, third generation virus respectively.The substratum that employing contains third generation virus infects Express
Figure BSA00000394448800623
The High Five that serum free medium is cultivated TMInsect cell is expressed target protein, collects the substratum that contains target protein after 72 hours, remains next step purifying.To contain level pad (20mM sodium phosphate (sodium phosphate) pH8.0 of the substratum (25-30mL) of target protein at 1L; 300mM NaCl, 10mM imidazoles (imidazole)) middle dialysed overnight, centrifugal 15 minutes of 12000rpm; Repeat once, collect supernatant.With appearance on the supernatant to through level pad equilibrated metal ion-chelant chromatography column (1mL HiTrap TMChelating HPcolumn (GE Healthcare; Life Sciences), after cleaning foreign protein, adopt elution buffer (20mM sodiumphosphate pH8.0,300mM NaCl; 250mM imidazole) to obtain target protein be beta-secretase extracellular region (BACE1) to wash-out; At last, through the albumen that 12% polyacrylamide gel electrophoresis (SDS-PAGE) isolation identification purifying obtains, purity is about 90%.
(2) determination of activity
DABCYL-Ser-Glu-Val-Asn-Leu-Asp-Ala-Glu-Phe-EDANS (Synpep is used in experiment; Under be called for short BS) as substrate; Surveying lives in being reflected in the 384 hole microwell plates carries out; Reaction volume is 25 μ l, contains 100mM sodium-acetate (sodium acetate) (pH 4.0)), 20 μ MBS, 50nM BACE-1,2 μ l methyl-sulphoxides (DMSO) or be dissolved in the testing compound (50 μ g/ml) of DMSO.Room temperature reaction is at the multi-functional plate instrument Envision that reads TM(PerkinElmer) detect fluorescent signal in; Excite with absorbing wavelength and be respectively 355nm and 460nm; Write down and calculate the increment of enzyme reaction initial stage unit time fluorescent signal, represent the enzyme reaction initial velocity, the active inhibiting rate of beta-secretase is represented the activity of this compound with testing compound with this; Wherein, inhibiting rate (inhibition) calculates and sees formula 1.
% Inhibition = ( 1 - v Compound v DMSD ) × 100 % Formula 1
υ in the formula 1 CompoundAnd υ DMSORepresentative contains the enzyme reaction initial velocity of compound and DMSO respectively.
If compound to be detected inhibiting rate when 20 μ g/mL further dilutes 7-9 concentration again greater than 50%, calculate IC 50, promptly the enzyme initial velocity is suppressed a half compound concentrations.Positive suppressor factor is compound OM99-2 (OM99-2 is the basis with octapeptide [L-glutamic acid-OMR99-1], has replaced the compound of leucine-L-Ala peptide bond with the isostere hydroxyalkyl vinyl base of a transition state).
Gained part of compounds activity is as shown in table 1:
Table 1
Figure BSA00000394448800632
Figure BSA00000394448800641
Figure BSA00000394448800651
Figure BSA00000394448800661
Figure BSA00000394448800681
Through the screening on molecular level, the discovery part of compounds shows has activity preferably to beta-secretase, and for further research possibly have the cognitive function of improvement, the original new drug of alleviating the AD PD simultaneously provides valuable information.

Claims (11)

1. hydroxyethyl triazole class compounds or aminoethyl triazole class compounds or its pharmacy acceptable salt represented like following general formula I:
Figure FSA00000394448700011
Wherein:
R 1For
Figure FSA00000394448700012
Figure FSA00000394448700013
Figure FSA00000394448700014
Wherein, X is NH, O or CH 2Y does
Figure FSA00000394448700015
Or CH 2R 6Be H, C 1-C 6Straight or branched alkyl or C 3-C 6Naphthenic base;
R 2For
Figure FSA00000394448700016
H, C 1-C 4Straight or branched alkyl, nitro, cyanic acid, ethanoyl or halogen; Wherein, R 7Be H, C 1-C 6Straight or branched alkyl or C 3-C 6Naphthenic base; R 8Be H, C 1-C 6Straight or branched alkyl or C 3-C 6Naphthenic base;
R 3Be C 1-C 6Straight or branched alkyl, phenyl or heteroaryl;
W and V are identical or different, are CH or N independently of one another;
Z is OH or NH 2
R 4And R 5Identical or different, be H, C independently of one another 1-C 6Straight or branched alkyl, phenyl, heteroaryl, C 3-C 6Naphthenic base, C 3-C 6Methyl cycloalkyl, C 1-C 6Carboxyl ester group, ethanoyl, N, N-dimethylaminomethyl, C 1-C 6Carboxamido-group, hydroxyl, amino, cyanic acid, trifluoromethyl, halogen,
Figure FSA00000394448700021
Wherein, n is the integer of 1-3, R 9Be H, ethanoyl, C 1-C 6Straight or branched alkyl, C 3-C 6Naphthenic base, C 6-C 10Aryl, heteroaryl, benzyl or α-acrinyl, R 10Be C 1-C 6Straight or branched alkyl, C 3-C 6Naphthenic base, the substituted Phenoxymethyl of trifluoromethyl, C 6-C 10Aryl or heteroaryl;
Wherein, said phenyl is not necessarily by C 1-C 6Straight or branched alkyl, halogen, trifluoromethyl, methoxyl group, amino or cyanic acid replace, said C 6-C 10Aryl is not necessarily by C 1-C 6Straight or branched alkyl, halogen, trifluoromethyl, methoxyl group, amino or cyanic acid replace, and said heteroaryl is to contain 1-3 heteroatomic five yuan or the six membered heteroaryl that is selected among N, S and the O.
2. hydroxyethyl triazole class compounds according to claim 1 or aminoethyl triazole class compounds or its pharmacy acceptable salt is characterized in that, Z is OH, when promptly said compound is the hydroxyethyl triazole class compounds:
W and V are respectively CH;
R 1For Wherein, X is NH; Y does
Figure FSA00000394448700023
R 6Be H or C 1-C 6The straight or branched alkyl;
R 2For
Figure FSA00000394448700024
Nitro or H; Wherein, R 7Be H, C 1-C 6Straight or branched alkyl or C 3-C 6Naphthenic base; R 8Be H, C 1-C 6Straight or branched alkyl or C 3-C 6Naphthenic base;
R 3Be phenyl;
R 4And R 5Identical or different, be H, C independently of one another 1-C 6Straight or branched alkyl, phenyl, heteroaryl, C 3-C 6Naphthenic base, C 3-C 6Methyl cycloalkyl, C 1-C 6Carboxyl ester group, ethanoyl, N, N-dimethylaminomethyl, C 1-C 6Carboxamido-group, hydroxyl, amino, cyanic acid, trifluoromethyl, halogen, Wherein n is the integer of 1-3, R 9Be H, ethanoyl, C 1-C 6Straight or branched alkyl, C 3-C 6Naphthenic base, C 6-C 10Aryl, heteroaryl, benzyl or α-acrinyl, R 10Be C 1-C 6Straight or branched alkyl, C 3-C 6Naphthenic base, the substituted Phenoxymethyl of trifluoromethyl, C 6-C 10Aryl or heteroaryl;
Wherein, said phenyl is not necessarily by C 1-C 6Straight or branched alkyl, halogen, trifluoromethyl, methoxyl group, amino or cyanic acid replace, said C 6-C 10Aryl is not necessarily by C 1-C 6Straight or branched alkyl, halogen, trifluoromethyl, methoxyl group, amino or cyanic acid replace, and said heteroaryl is to contain 1-3 heteroatomic five yuan or the six membered heteroaryl that is selected among N, S and the O.
3. hydroxyethyl triazole class compounds according to claim 1 or aminoethyl triazole class compounds or its pharmacy acceptable salt is characterized in that, Z is NH 2, when promptly said compound is the aminoethyl triazole class compounds:
W and V are respectively CH;
R 1For
Figure FSA00000394448700031
Wherein, X is NH; Y does
Figure FSA00000394448700032
R 6Be H or C 1-C 6The straight or branched alkyl;
R 2For
Figure FSA00000394448700033
Nitro or H; Wherein, R 7Be H, C 1-C 6Straight or branched alkyl or C 3-C 6Naphthenic base; R 8Be H, C 1-C 6Straight or branched alkyl or C 3-C 6Naphthenic base;
R 3Be phenyl;
R 4And R 5Identical or different, be H, C independently of one another 1-C 6Straight or branched alkyl, phenyl, heteroaryl, C 3-C 6Naphthenic base, C 3-C 6Methyl cycloalkyl, C 1-C 6Carboxyl ester group, ethanoyl, N, N-dimethylaminomethyl, C 1-C 6Carboxamido-group, hydroxyl, amino, cyanic acid, trifluoromethyl, halogen,
Figure FSA00000394448700034
Wherein n is the integer of 1-3, R 9Be H, ethanoyl, C 1-C 6Straight or branched alkyl, C 3-C 6Naphthenic base, C 6-C 10Aryl, heteroaryl, benzyl or α-acrinyl, R 10Be C 1-C 6Straight or branched alkyl, C 3-C 6Naphthenic base, F 3C substituted benzene oxygen methyl, C 6-C 10Aryl or heteroaryl;
Wherein, said phenyl is not necessarily by C 1-C 6Straight or branched alkyl, halogen, trifluoromethyl, methoxyl group, amino or cyanic acid replace, said C 6-C 10Aryl is not necessarily by C 1-C 6Straight or branched alkyl, halogen, trifluoromethyl, methoxyl group, amino or cyanic acid replace, and said heteroaryl is to contain 1-3 heteroatomic five yuan or the six membered heteroaryl that is selected among N, S and the O.
4. according to claim 2 or 3 described hydroxyethyl triazole class compounds or aminoethyl triazole class compounds or its pharmacy acceptable salt, it is characterized in that,
Said R 4And R 5Identical or different, be H, C independently of one another 1-C 6Straight or branched alkyl, phenyl, heteroaryl, C 3-C 6Naphthenic base, C 3-C 6Methyl cycloalkyl, C 1-C 6Carboxyl ester group, ethanoyl, N, N-dimethylaminomethyl, C 1-C 6Carboxamido-group, hydroxyl, amino, cyanic acid, trifluoromethyl, halogen,
Figure FSA00000394448700041
Wherein n is the integer of 1-3, R 9Be H, ethanoyl, C 1-C 6Straight or branched alkyl, C 3-C 6Naphthenic base, phenyl, benzyl or α-acrinyl, R 10Be C 1-C 6Straight or branched alkyl, C 3-C 6The substituted Phenoxymethyl of naphthenic base, phenyl or trifluoromethyl;
Wherein, said phenyl is not necessarily by C 1-C 6Straight or branched alkyl, halogen, trifluoromethyl, methoxyl group, amino or cyanic acid replace, and said heteroaryl is to contain 1-3 heteroatomic five yuan or the six membered heteroaryl that is selected among N, S and the O.
5. according to each described hydroxyethyl triazole class compounds or aminoethyl triazole class compounds or its pharmacy acceptable salt in the claim 1～3; It is characterized in that said hydroxyethyl triazole class compounds or aminoethyl triazole class compounds are one of following compound:
Figure FSA00000394448700042
Figure FSA00000394448700071
Figure FSA00000394448700081
Figure FSA00000394448700091
6. the preparation method of hydroxyethyl triazole class compounds as claimed in claim 2 is characterized in that, this method is used following synthetic route 1,2 or 3:
Synthetic route 1:
Figure FSA00000394448700101
Reactions step is following:
A) be starting raw material with epoxy compounds A, with sodiumazide in the presence of ammonium chloride be that solvent refluxing reaction open loop gets compd B with methyl alcohol,
B) compd B is sloughed the basic Compound C that gets of Boc protection under acidic conditions,
C) under the condition that one or more compounds exist in EDCI, HOBt and DIPEA, Compound C further gets Compound D with R1 and the substituted phenylformic acid condensation of R2,
D) the synthetic of 4-position replacement hydroxyethyl triazole compounds E is catalyzer with the mantoquita, and anti-sepsis acid sodium is reductive agent, makes Compound D at THF/H 2Reacted 24-48 hour down in 50 ℃ of reactions in the O mixed solvent, obtain through silicagel column or thin plate layer analysis method;
Synthetic route 2:
Figure FSA00000394448700102
Wherein, reactions step a), b), c) the same, at reactions step d) in:
The 5-position replaces the synthetic with Ru (PPh of hydroxyethyl triazole class compounds F 3) 2Cl 2Being catalyzer, is solvent with THF, make Compound D the heating condition under with
Figure FSA00000394448700111
Reacted 12-24 hour, and obtained through silicagel column or thin plate layer analysis method;
Perhaps, synthetic route 3:
Figure FSA00000394448700112
Wherein, reactions step a), b), c) the same, at reactions step d) in:
4; It is alternatively by copper catalysis that 5-two replaces the synthetic of hydroxyethyl triazole class compounds G; And be solvent with toluene directly, reaction obtains with
Figure FSA00000394448700113
under the condition of heating to make Compound D.
7. the preparation method of aminoethyl triazole class compounds as claimed in claim 3 is characterized in that, this method is used following synthetic route:
Figure FSA00000394448700121
Reactions step is following:
A) be starting raw material with epoxy compounds H, with phthalic diamide in the presence of triphenyl phosphorus, azoformic acid isopropyl ester, be that solvent gets compound I in the room temperature reaction open loop with THF,
B) compound I is sloughed the basic compound J of getting of Boc protection under acidic conditions,
C) compound J further with R1 and the substituted phenylformic acid of the R2 condition that one or more compounds exist in EDCI, HOBt and DIPEA under condensation get compound K,
D) the synthetic of 4-position replacement aminoethyl triazole class compounds L is to be catalyzer with the mantoquita, and anti-sepsis acid sodium is reductive agent, makes compound K at THF/H 2Reacted 24-48 hour down in 50 ℃ of reactions in the O mixed solvent, obtain through silicagel column or thin plate layer analysis method.
8. according to claim 6 or 7 described methods, it is characterized in that said mantoquita is cupric sulfate pentahydrate or cuprous iodide.
9. according to claim 6 or 7 described methods, it is characterized in that acidic conditions described in the step b) is the condition at trifluoroacetic acid or hydrochloric acid.
10. described hydroxyethyl triazole class compounds of claim 1 or aminoethyl triazole class compounds or its pharmacy acceptable salt are used for preventing, delay or treat the purposes of the medicine of the disease that the deposition by A β causes in preparation.
11. purposes according to claim 10, the wherein said disease that is caused by the deposition of A β is a presenile dementia.
CN201010599930.5A 2010-12-20 2010-12-20 Ethoxyl-triazole compound or amonoethyl-triazole compound and preparation method and application thereof Expired - Fee Related CN102558157B (en)

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CN1671377A (en) * 2002-09-19 2005-09-21 索尔瓦药物有限公司 1H-1,2,4-triazole-3-carboxamide derivatives as cannabinoid-CB receptor ligands

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