CN102558157B - 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 PDFInfo
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- 0 CC(C)(C)OC(N[C@@](Cc1ccccc1)[C@@](C*)O)=O Chemical compound CC(C)(C)OC(N[C@@](Cc1ccccc1)[C@@](C*)O)=O 0.000 description 7
- XKJCHHZQLQNZHY-UHFFFAOYSA-N O=C(c1ccccc11)NC1=O Chemical compound O=C(c1ccccc11)NC1=O XKJCHHZQLQNZHY-UHFFFAOYSA-N 0.000 description 2
- REMKUQRPKHMURU-YPKYBTACSA-N CC(C)(C)c1c[n](C[C@@H]([C@H](Cc2ccccc2)NC(c2cc(N(C)S(C)(=O)=O)cc(C(N[C@@H](c3ccccc3)C#C)=O)c2)=O)N)nn1 Chemical compound CC(C)(C)c1c[n](C[C@@H]([C@H](Cc2ccccc2)NC(c2cc(N(C)S(C)(=O)=O)cc(C(N[C@@H](c3ccccc3)C#C)=O)c2)=O)N)nn1 REMKUQRPKHMURU-YPKYBTACSA-N 0.000 description 1
- BCSHNWDMCGOGRC-UHFFFAOYSA-O CC(c(cc1)ccc1F)NC(c1cc([NH+](C)CS(C)=O)cc(C(NC(Cc2ccccc2)C(C[n]2nnc(-c3ccccc3)c2)=O)=O)c1)=O Chemical compound CC(c(cc1)ccc1F)NC(c1cc([NH+](C)CS(C)=O)cc(C(NC(Cc2ccccc2)C(C[n]2nnc(-c3ccccc3)c2)=O)=O)c1)=O BCSHNWDMCGOGRC-UHFFFAOYSA-O 0.000 description 1
- LPZHGUBDOMZCPU-UPGTZSEYSA-N CCCC(/C(/N)=C/N(C[C@@H]([C@H](C)NC(c1cc(C(N[C@H](C)c2ccccc2)=O)cc(N(C)S(C)(=O)=O)c1)=O)O)N)O Chemical compound CCCC(/C(/N)=C/N(C[C@@H]([C@H](C)NC(c1cc(C(N[C@H](C)c2ccccc2)=O)cc(N(C)S(C)(=O)=O)c1)=O)O)N)O LPZHGUBDOMZCPU-UPGTZSEYSA-N 0.000 description 1
- RNIYHEMMFDXHQP-CYBMUJFWSA-N CCO[C@H](Cc1ccccc1)NC(OC(C)(C)C)=O Chemical compound CCO[C@H](Cc1ccccc1)NC(OC(C)(C)C)=O RNIYHEMMFDXHQP-CYBMUJFWSA-N 0.000 description 1
- MFILQRYGXCVUHI-DBMGCCQASA-N C[C@@H](c1c[n](C[C@@H](C(C#Cc2ccccc2)NC(c2cc(N(C)S(C)(=[U])=[U])cc(C(N[C@H](C)c3ccccc3)=O)c2)=O)O)nn1)O Chemical compound C[C@@H](c1c[n](C[C@@H](C(C#Cc2ccccc2)NC(c2cc(N(C)S(C)(=[U])=[U])cc(C(N[C@H](C)c3ccccc3)=O)c2)=O)O)nn1)O MFILQRYGXCVUHI-DBMGCCQASA-N 0.000 description 1
- SDXBDSLOVIJSLJ-YHIVJRRQSA-N C[C@H](c(cc1)ccc1F)NC(c1cc(N(C)S(C)(=O)=O)cc(C(N[C@@H](Cc2ccccc2)[C@H](C[n]2nnc(COc3ccccc3)c2)O)=O)c1)=O Chemical compound C[C@H](c(cc1)ccc1F)NC(c1cc(N(C)S(C)(=O)=O)cc(C(N[C@@H](Cc2ccccc2)[C@H](C[n]2nnc(COc3ccccc3)c2)O)=O)c1)=O SDXBDSLOVIJSLJ-YHIVJRRQSA-N 0.000 description 1
- PRVCUKXQVMSENF-ZHAMFGDSSA-N Cc1cccc(-c2c[n](C[C@@H]([C@H](Cc3ccccc3)NC(c3cc(N(C)S(C)(=O)=O)cc(C(N[C@@H](c(cc4)ccc4F)C#C)=O)c3)=O)O)nn2)c1 Chemical compound Cc1cccc(-c2c[n](C[C@@H]([C@H](Cc3ccccc3)NC(c3cc(N(C)S(C)(=O)=O)cc(C(N[C@@H](c(cc4)ccc4F)C#C)=O)c3)=O)O)nn2)c1 PRVCUKXQVMSENF-ZHAMFGDSSA-N 0.000 description 1
Classifications
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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
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02P—CLIMATE CHANGE MITIGATION TECHNOLOGIES IN THE PRODUCTION OR PROCESSING OF GOODS
- Y02P20/00—Technologies relating to chemical industry
- Y02P20/50—Improvements relating to the production of bulk chemicals
- Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups
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. The constitutional formula is shown in the description.
Description
Technical field
The present invention relates to hydroxyethyl triazole class compounds or aminoethyl triazole class compounds and its production and use.
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 abnormal etc.The elderly's health in its serious threat, especially 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, although can reverse study, memory impairment that choline function damage causes, 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, the generation of the amyloid beta in brain (β-amyloid peptide, hereinafter referred A β) and gathering are considered to an important factor that causes this disease to produce.A β is that 11-15 amino acid of its end is positioned at the cross-film district of APP by the polypeptide of the approximately 4kD of amyloid precursor protein (amyloidprecursor protein, hereinafter referred APP) hydrolysis generation.Mainly contain three kinds of Secretasess and participated in the hydrolytic process to APP, be called α, β and gamma-secretase.The restriction enzyme site of alpha-secretase enzyme is positioned at A β sequence, produces soluble α-APP fragment and C83 peptide after acting on APP, and C83 peptide can continue to be generated P3 peptide by gamma-secretase hydrolysis, does not produce A β.And the restriction enzyme site of beta-secretase is positioned at A β N and holds first amino acid, produce β-APP and C99 peptide after acting on APP, C99 peptide produces A β through gamma-secretase effect again.As can be seen here, beta-secretase is very crucial rate-limiting enzyme in A β forming process.And the mouse that knocks out beta-secretase gene shows there is no the generation of the A β while completely without the obstacle of obvious nerve and other physiological function aspect, 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 inhibitor 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 existing in prior art, the inventor has designed and synthesized a series of beta-secretase inhibitors, to reaching the object for the treatment of AD.
Therefore, an object of the present invention is to provide and a kind of beta-secretase is had to inhibiting hydroxyethyl triazole class compounds or aminoethyl triazole class compounds or its pharmacy acceptable salt.
Another object of the present invention is to provide the preparation method of this compounds.
A further object of the present invention is to provide this compounds as the purposes of beta-secretase inhibitor, and it is as the medicinal application for the treatment of AD.
For achieving the above object, the invention provides hydroxyethyl triazole class compounds or aminoethyl triazole class compounds or its pharmacy acceptable salt representing as following general formula I:
Wherein:
R
1for
wherein, X is NH, O or CH
2; Y is
or CH
2; R
6for H, C
1-C
6straight or branched alkyl or C
3-C
6cycloalkyl;
R
2for
h, C
1-C
4straight or branched alkyl, nitro, cyano group, ethanoyl or halogen; Wherein, R
7for H, C
1-C
6straight or branched alkyl or C
3-C
6cycloalkyl; R
8for H, C
1-C
6straight or branched alkyl or C
3-C
6cycloalkyl;
R
3for 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
6cycloalkyl, C
3-C
6methyl cycloalkyl, C
1-C
6carboxyl ester group, ethanoyl, N, N-dimethylaminomethyl, C
1-C
6amide group, hydroxyl, amino, cyano group, trifluoromethyl, halogen,
the integer that wherein n is 1-3, R
9for H, ethanoyl, C
1-C
6straight or branched alkyl, C
3-C
6cycloalkyl, C
6-C
10aryl, heteroaryl, benzyl or α-acrinyl, R
10for C
1-C
6straight or branched alkyl, C
3-C
6phenoxymethyl, C that cycloalkyl, trifluoromethyl replace
6-C
10aryl or heteroaryl;
Wherein, described phenyl is not necessarily by C
1-C
6straight or branched alkyl, halogen, trifluoromethyl, methoxyl group, amino or cyano group replace, described C
6-C
10aryl is not necessarily by C
1-C
6straight or branched alkyl, halogen, trifluoromethyl, methoxyl group, amino or cyano group replace, and described heteroaryl is to contain 1-3 heteroatomic five yuan or the six membered heteroaryl being selected from N, S and O.
In the preferred embodiment of the present invention one, in above-mentioned general structure, Z is OH, and described compound is hydroxyethyl triazole class compounds;
And further preferred:
W and V are respectively CH;
R
1for
wherein, X is NH; Y is
r
6for H or C
1-C
6straight or branched alkyl;
R
2for
nitro or H; Wherein, R
7for H, C
1-C
6straight or branched alkyl or C
3-C
6cycloalkyl; R
8for H, C
1-C
6straight or branched alkyl or C
3-C
6cycloalkyl;
R
3for 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
6cycloalkyl, C
3-C
6methyl cycloalkyl, C
1-C
6carboxyl ester group, ethanoyl, N, N-dimethylaminomethyl, C
1-C
6amide group, hydroxyl, amino, cyano group, trifluoromethyl, halogen,
the integer that wherein n is 1-3, R
9for H, ethanoyl, C
1-C
6straight or branched alkyl, C
3-C
6cycloalkyl, C
6-C
10aryl, heteroaryl, benzyl or α-acrinyl, R
10for C
1-C
6straight or branched alkyl, C
3-C
6cycloalkyl, F
3phenoxymethyl, C that C replaces
6-C
10aryl or heteroaryl;
Wherein, described phenyl is not necessarily by C
1-C
6straight or branched alkyl, halogen, trifluoromethyl, methoxyl group, amino or cyano group replace, described C
6-C
10aryl is not necessarily by C
1-C
6straight or branched alkyl, halogen, trifluoromethyl, methoxyl group, amino or cyano group replace, and described heteroaryl is to contain 1-3 heteroatomic five yuan or the six membered heteroaryl being selected from N, S and O.
In another preferred embodiment of the present invention, described R
4and R
5identical or different, be H, C independently of one another
1-C
6straight or branched alkyl, phenyl, heteroaryl, C
3-C
6cycloalkyl, C
3-C
6methyl cycloalkyl, C
1-C
6carboxyl ester group, ethanoyl, N, N-dimethylaminomethyl, C
1-C
6amide group, hydroxyl, amino, cyano group, trifluoromethyl, halogen,
the integer that wherein n is 1-3, R
9for H, ethanoyl, C
1-C
6straight or branched alkyl, C
3-C
6cycloalkyl, phenyl, benzyl or α-acrinyl, R
10for C
1-C
6straight or branched alkyl, C
3-C
6cycloalkyl, phenyl or F
3the Phenoxymethyl that C replaces; Wherein, described phenyl is not necessarily by C
1-C
6straight or branched alkyl, halogen, trifluoromethyl, methoxyl group, amino or cyano group replace, and described heteroaryl is to contain 1-3 heteroatomic five yuan or the six membered heteroaryl being selected from N, S and O.
According to another object of the present invention, the invention provides the preparation method of hydroxyethyl triazole class compounds, the method is used following synthetic route 1,2 or 3:
Synthetic route 1:
Reactions steps is as follows:
A) take epoxy compounds A as starting raw material, the methyl alcohol of take under ammonium chloride exists with sodiumazide obtains compd B as solvent refluxing reacts open loop,
B) B, under acidic conditions, preferably sloughs Boc protecting group and obtains Compound C under the condition of trifluoroacetic acid or hydrochloric acid,
C) at EDCI (1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride), HOBt (1-hydroxy benzo triazole) and DIPEA (N, N-diisopropylethylamine) under the condition that in, one or more compounds exist, Compound C further obtains Compound D with the phenylformic acid condensation that R1 and R2 replace
D) the synthetic of hydroxyethyl triazole class compounds E that 4-position replaces is with copper salt catalyst, and anti-sepsis acid sodium is reductive agent, makes Compound D at THF (tetrahydrofuran (THF))/H
2in O mixed solvent, under 50 ℃ of reactions, react 24-48 hour, by silicagel column or thin plate layer analysis method, obtain, wherein, the preferred cupric sulfate pentahydrate of described mantoquita or cuprous iodide.
Synthetic route 2:
Wherein, reactions steps a), b), c) the same, reactions steps d) in:
It is with Ru (PPh that 5-position replaces the synthetic of hydroxyethyl triazole class compounds F
3)
2cl
2for catalyzer, take THF as solvent, make Compound D heating condition under with
reaction 12-24 hour, obtains by silicagel column or thin plate layer analysis method;
Or, synthetic route 3:
Wherein, reactions steps a), b), c) the same, reactions steps d) in:
The dibasic hydroxyethyl triazole class compounds of 4,5-G synthetic is alternatively by copper catalysis, directly take toluene as solvent, make Compound D under the condition of heating with
reaction obtains, and wherein, two substitution compounds that 5-position iodine replaces obtain under copper catalysis.
In the present invention, again in a preferred embodiment, in above-mentioned general structure, Z is NH
2, described compound is aminoethyl triazole class compounds;
And further preferred:
W and V are respectively CH;
R
1for
wherein, X is NH; Y is
r
6for H or C
1-C
6straight or branched alkyl;
R
2for
nitro or H; Wherein, R
7for H, C
1-C
6straight or branched alkyl or C
3-C
6cycloalkyl; R
8for H, C
1-C
6straight or branched alkyl or C
3-C
6cycloalkyl;
R
3for 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
6cycloalkyl, C
3-C
6methyl cycloalkyl, C
1-C
6carboxyl ester group, ethanoyl, N, N-dimethylaminomethyl, C
1-C
6amide group, hydroxyl, amino, cyano group, trifluoromethyl, halogen,
the integer that wherein n is 1-3, R
9for H, ethanoyl, C
1-C
6straight or branched alkyl, C
3-C
6cycloalkyl, C
6-C
10aryl, heteroaryl, benzyl or α-acrinyl, R
10for C
1-C
6straight or branched alkyl, C
3-C
6cycloalkyl, F
3phenoxymethyl, C that C replaces
6-C
10aryl or heteroaryl;
Wherein, described phenyl is not necessarily by C
1-C
6straight or branched alkyl, halogen, trifluoromethyl, methoxyl group, amino or cyano group replace, described C
6-C
10aryl is not necessarily by C
1-C
6straight or branched alkyl, halogen, trifluoromethyl, methoxyl group, amino or cyano group replace, and described heteroaryl is to contain 1-3 heteroatomic five yuan or the six membered heteroaryl being selected from N, S and O.
In the another preferred embodiment of the present invention, described R
4and R
5identical or different, be H, C independently of one another
1-C
6straight or branched alkyl, phenyl, heteroaryl, C
3-C
6cycloalkyl, C
3-C
6methyl cycloalkyl, C
1-C
6carboxyl ester group, ethanoyl, N, N-dimethylaminomethyl, C
1-C
6amide group, hydroxyl, amino, cyano group, trifluoromethyl, halogen,
the integer that wherein n is 1-3, R
9for H, ethanoyl, C
1-C
6straight or branched alkyl, C
3-C
6cycloalkyl, phenyl, benzyl or α-acrinyl, R
10for C
1-C
6straight or branched alkyl, C
3-C
6cycloalkyl, phenyl or F
3the Phenoxymethyl that C replaces; Wherein, described phenyl is not necessarily by C
1-C
6straight or branched alkyl, halogen, trifluoromethyl, methoxyl group, amino or cyano group replace, and described heteroaryl is to contain 1-3 heteroatomic five yuan or the six membered heteroaryl being selected from N, S and 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 by following route:
Reactions steps is as follows:
A) take epoxy compounds H as starting raw material, at triphenyl phosphorus, the THF of take under azoformic acid isopropyl ester exists obtains Compound I in room temperature reaction open loop as solvent with phthalic diamide,
B) Compound I, under acidic conditions, is preferably sloughed Boc protecting group and is obtained compound J under the condition of trifluoroacetic acid or hydrochloric acid,
C) compound J further obtains compound K with phenylformic acid condensation under EDCI, HOBt, DIPEA exist that R1 and R2 replace,
D) the synthetic of 4-position replacement aminoethyl triazole class compounds L is to take mantoquita as catalyzer, and anti-sepsis acid sodium is reductive agent, makes compound K at THF/H
2in the mixed solvent of O, under 50 ℃ of reactions, react 24-48 hour, by silicagel column or thin plate layer analysis method, obtain, wherein, the preferred cupric sulfate pentahydrate of described 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:
According to a further object of the present invention, the invention provides this compounds as beta-secretase inhibitor, for the preparation of prevention, delay or treat by the purposes in the disease, particularly AD medicine of the deposition initiation of A β.
Hydroxyethyl triazole class compounds of the present invention or aminoethyl triazole class compounds, the activity with obvious inhibition beta-secretase, this may have for further research the cognitive function of improvement, and the original new drug of simultaneously alleviating AD progression of disease provides valuable information.
Embodiment
Below in conjunction with embodiment, the present invention is further elaborated, and following embodiment is only described the present invention by way of example.Clearly, those of ordinary skills can, in scope of the present invention and essence, carry out various accommodations and modification to the present invention.Need to be appreciated that, this invention is intended to be encompassed in the flexible and modification that appended claims comprises.
Experiment and sample analysis instrument:
Nuclear magnetic resonance spectrum (1H NMR) is by 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.
Optically-active data are measured by PerkinElmer-341 type polarimeter.
Column chromatography for separation used silica gel is Haiyang Chemical Plant, Qingdao's product (200-300 order).
TLC silica-gel plate is the HSF-254 thin-layer chromatography precoated plate of Yantai Chemical Manufacture.
Ultraviolet lamp is the Shanghai ZF-1 of Gu Cun electric light instrument plant type ultraviolet analysis instrument for three purposed.
Microwave reactor is Biotage Initiator product.
Preparation Example (embodiments of the invention are numbered same compound number)
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic route:
Reactions steps:
By epoxy compounds (2S, 3S)-1,2-epoxy-3-(N-tertiary butyloxycarbonyl is amino)-4-phenylpropyl alcohol alkane (770mg, 2.93mmol) is dissolved in 20mL methyl alcohol, in system, adds NH
4cl (282mg, 5.27mmol), NaN
3(457mg, 7.03mmol).Be heated to reflux state, reaction is spent the night to remaining without raw material.Reaction solution is concentrated, in system, add 30mL water, ethyl acetate extraction 2 times, each 30mL (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, filter, concentrated, obtain white solid (2S, 3S)-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)。
Above-mentioned trinitride (92mg, 0.3mmol) is dissolved in 4mL methylene dichloride, in system, adds 1mL trifluoroacetic acid, room temperature reaction 3h.Concentrated, the amine obtaining is not treated directly enters next step reaction.By 5-(methyl methylsulfonyl) amino-3-((1R)-1-(4-fluorophenyl)) ethyl aminocarbonyl phenylformic acid (106mg; 0.27mmol) be dissolved in 2mL DMF; add EDCI (52mg; 0.27mmol), HOBt (37mg; 0.27mmol), stirring at room 10min.The amine that upper step is obtained is dissolved in the DMF of 2mL, adds DIPEA (99 μ l, 0.6mmol), is splashed into above-mentioned reaction system, then the lower 70 ℃ of reaction 15min of microwave condition.In system, add 30mL water, ethyl acetate extraction (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, filter, concentrated, 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, by 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 THF of 800 μ L and the water of 200 μ L, after stirring, the anti-sepsis acid sodium (2mg that adds 0.2 equivalent, 0.01mmol), the cuprous iodide (1mg, 0.005mmol) of 0.2 equivalent.Reaction is reacted 12-24h under the condition of 50 ℃ of heating, directly by TLC (thin-layer chromatography, thin plate chromatography) chromatography, obtains end product, yield: 91.5%.
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 1, is just replaced phenylacetylene, yield: 81.2% with cyclohexyl methyl alkynes.
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 1, is just replaced phenylacetylene with ethyl propiolate, yield: 72.4%.
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route is with reference to described in embodiment 1, and just with N, N-dimethyl propargylamine is replaced 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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route is with reference to described in 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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route is with reference to described in 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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route is with reference to described in 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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route is with reference to described in 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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
According to synthetic route 1, the triazo-compound N-[(1S making with reference to embodiment 1,2S)-1-benzyl-2-hydroxyl-3-azido-]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine (29mg, 0.05mmol) with trimethylsilyl acetylene (28 μ L, 0.2mmol) join in the THF of 800 μ L and the water of 200 μ L, after stirring, the anti-sepsis acid sodium (2mg that adds 0.2 equivalent, 0.01mmol), the cupric sulfate pentahydrate (1mg, 0.005mmol) of 0.1 equivalent.Reaction is reacted 12-24h under the condition of 50 ℃ of heating, after completion of the reaction that solvent is concentrated, directly carries out next step reaction.To the THF that adds 1mL in above-mentioned system, tetrabutyl ammonium fluoride Bu
4nF (52mg, 0.2mmol), reaction is spent the night, and directly by TLC chromatography, obtains end product 21mg, yield: 70.0%.
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
According to synthetic route 1, the triazo-compound N-[(1S making with reference to embodiment 1,2S)-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 THF of 800 μ L and the water of 200 μ L, after stirring, the anti-sepsis acid sodium (2mg that adds 0.2 equivalent, 0.01mmol), the cupric sulfate pentahydrate (1mg, 0.005mmol) of 0.1 equivalent.Reaction is reacted 12-24h under the condition of 50 ℃ of heating, directly by TLC chromatography, obtains end product 23mg, yield: 71.5%.
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 74.8% with 4-methyl-1-pentene alkynes (17 μ L, 0.2mmol).
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 70.1% with propargyl alcohol (12 μ L, 0.2mmol).
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 65.2% with propargyl acetate (29 μ L, 0.2mmol).
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 86.4% with phenyl propargyl ether (26 μ L, 0.2mmol).
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
According to synthetic route 2, carry out:
The triazo-compound N-[(1S making with reference to embodiment 1,2S)-1-benzyl-2-hydroxyl-3-azido-]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine (29mg, 0.05mmol) and phenylacetylene (22 μ L, 0.2mmol) and Ru (PPh
3)
2cl
2(4mg, 0.005mmol) joins in the THF of 1mL, and back flow reaction 8h under the protection of argon gas, directly obtains end product 20mg by 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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 15, is replaced phenylacetylene, yield: 46.3% with ethyl propiolate (20 μ L, 0.2mmol).
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 15, is replaced phenylacetylene, yield: 51.1% with propargyl alcohol (12 μ L, 0.2mmol).
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 15, is replaced phenylacetylene, yield: 50.6% with phenyl propargyl ether (26 μ L, 0.2mmol).
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-triazolyl)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
According to synthetic route 3, carry out:
The triazo-compound N-[(1S making with reference to embodiment 1,2S)-1-benzyl-2-hydroxyl-3-azido-]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine (29mg, 0.05mmol) and dimethyl butyn (24 μ L, 0.2mmol) join in the toluene of 1mL.Reaction is reacted 24h under the condition of 100 ℃ of heating, directly by TLC chromatography, obtains end product 24mg, yield: 66.3%.
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 19, is replaced dimethyl butyn, yield: 55.6% with 2-butyne-Isosorbide-5-Nitrae-glycol (16mg, 0.2mmol).
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
In embodiment 21 and 22, the synthesis step of compound, with embodiment 19, is just replaced dimethyl butyn by 4-benzyloxy-2-butyne-1-alcohol, and wherein, the synthetic route of 4-benzyloxy-2-butyne-1-alcohol is as follows:
Synthesizing of 4-benzyloxy-2-butyne-1-alcohol: potassium hydroxide (3.67g, 67mmol) is dissolved in the water of 50mL, adds respectively Isosorbide-5-Nitrae-butynediol (5.78g, 67.2mmol) and benzyl bromine (2mL, 16.8mmol), room temperature reaction 48h.Add dichloromethane extraction (40mL * 3), merge organic phase, saturated common salt washing (20mL * 1) for organic phase, anhydrous magnesium sulfate drying, filters, concentrated, crosses post and obtains colorless oil 2.0g, yield: 67.7% with petrol ether/ethyl acetate=1/5.
1H?NMR(300MHz，CDCl3)：δ7.25(m，5H)，4.60(s，2H)，4.32(m，2H)，4.22(m，2H)。
4-benzyloxy-2-butyne-1-alcohol (34mg, 0.2mmol) is replaced to dimethyl butyn, be separated to positional isomers 172:13mg, 173:14mg from reaction solution simultaneously, yield is respectively: 34.3%, 36.9%.
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-triazolyl)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthesizing of N-iodo morpholine hydriodate: iodine (25.4,0.10mmol) be dissolved in the methyl alcohol of 400mL, progressively splash into morpholine (8.71mL, 0.10mol).In the process dripping, solution is become faint yellow from dark-brown, and has yellow Precipitation.After dropwising, at room temperature continue reaction 1h.Filter, the solid obtaining is product, dry in a vacuum, obtains product 26.8g, yield: 78.7%.
Synthesizing of the iodo-3-butyne-2-alcohol of 4-: 3-butyne-2-alcohol (560mg, 8mmol) is dissolved in 20mLTHF, adds cuprous iodide (76mg, 0.4mmol) and N-iodo morpholine hydriodate (3.0g, 8.8mmol).2h is at room temperature carried out in reaction.Diatomite filtration, concentrates to obtain 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-[(1S making with reference to embodiment 1,2S)-1-benzyl-2-hydroxyl-3-azido-]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine (582mg, 1mmol) with the iodo-3-butyne-2-alcohol of 4-(220mg, 1.1mmol) be dissolved in 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.Concentrated, add water (20mL), dichloromethane extraction (20mL * 3), merges organic phase, with saturated common salt washing, anhydrous sodium sulfate drying, filters, concentrated, with petrol ether/ethyl acetate=1/1-0/1, cross post, obtain white solid 550mg, yield: 70.7%.Fusing point: 100-103 ℃.
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 91.5% with 3-methylbenzene acetylene (26 μ L, 0.2mmol).
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 94.2% with 4-fluorobenzene acetylene (23 μ L, 0.2mmol).
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-triazolyl)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 90.2% with 4-anisole acetylene (26 μ L, 0.2mmol).
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 82.1% with pyridine-2-acetylene (20 μ L, 0.2mmol).
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 82.3% with tert-butyl acetylene (25 μ L, 0.2mmol).
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 64.5% with 3-methyl isophthalic acid-acetylene (19 μ L, 0.2mmol).
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 62.7% with 1-pentyne (20 μ L, 0.2mmol).
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 86.2% with cyclopentyl acetylene (23 μ L, 0.2mmol).
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 86.2% with cyclohexyl-acetylene (26 μ L, 0.2mmol).
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 74.3% with 3-butyne-1-ol (15 μ L, 0.2mmol).
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 78.5% with 4-pentyne-1-alcohol (18 μ L, 0.2mmol).
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
According to synthetic route 1, the triazo-compound N-[(1S making with reference to embodiment 1,2S)-1-benzyl-2-hydroxyl-3-azido-]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine (29mg, 0.05mmol) with 2-propargylamine base t-butyl formate (16mg, 0.1mmol) join in the THF of 800 μ L and the water of 200 μ L, after stirring, the anti-sepsis acid sodium (2mg that adds 0.2 equivalent, 0.01mmol), the cupric sulfate pentahydrate (1mg, 0.005mmol) of 0.1 equivalent.Reaction is reacted 24h under the condition of 50 ℃ of heating, concentrated.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), concentrated, directly by TLC chromatography, obtain end product 25mg, 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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 68.9% by 3-crotonylene-one (15 μ L, 0.2mmol).
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-triazolyl)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 80.1% with 2-methyl-3-butyne-2-alcohol (19 μ L, 0.2mmol).
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-triazolyl)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 86.7% with methylpentynol (23 μ L, 0.2mmol).
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 85.5% with 3,4-dimethyl-1-pentyne-3-alcohol (25 μ L, 0.2mmol).
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-triazolyl)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 83.2% with 1-ethynyl-1-cyclopentanol (23 μ L, 0.2mmol).
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 73.1% with 3-butyne-2-alcohol (16 μ L, 0.2mmol).
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 78.7% with 1-pentyne-3-alcohol (19 μ L, 0.2mmol).
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 80.1% with 1-hexin-3-alcohol (19 μ L, 0.2mmol).
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-triazolyl)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 76.3% with 4-methyl-1-pentene alkynes-3-alcohol (21 μ L, 0.2mmol).
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 81.2% with 1-heptyne-3-alcohol (26 μ L, 0.2mmol).
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-triazolyl)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 81.2% with 5-methyl isophthalic acid-hexin-3-alcohol (25 μ L, 0.2mmol).
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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
By epoxy compounds (2S, 3R)-1,2-epoxy-3-(N-tertiary butyloxycarbonyl is amino)-4-phenylpropyl alcohol alkane (6g, 22.8mmol) is dissolved in 120mL methyl alcohol, in system, adds NH
4cl (2.22g, 41.5mmol), NaN
3(3.72g, 57.2mmol).Be heated to reflux state, reaction is spent the night to remaining without raw material.Reaction solution is concentrated into volume and is about 60mL, in the process stirring, in system, add water to 250mL, have a large amount of white solids to separate out.Filter, infrared drying, obtains 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)。
Trinitride (2S, 3R)-1-benzyl-2-hydroxyl-3-azido-t-butyl carbamate (306mg, 1mmol) is dissolved in 4mL methylene dichloride, in system, adds 1mL trifluoroacetic acid, room temperature reaction 3h.Concentrated, the amine that obtains is unprocessed directly enters next step reaction.
By 5-(methyl methylsulfonyl) amino-3-((1R)-1-(4-fluorophenyl)) ethyl aminocarbonyl phenylformic acid (354mg; 0.9mmol) be dissolved in 2mL DMF; add EDCI (173mg; 0.9mmol); HOBt (122mg; 0.9mmol), stirring at room 10min.The amine that upper step is obtained is dissolved in the DMF of 2mL, adds DIPEA (258mg, 2mmol), is splashed into above-mentioned reaction system, then the lower 70 ℃ of reaction 15min of microwave condition.In system, add 30mL water, ethyl acetate extraction (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, filter, concentrated, column chromatography obtains 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) replace N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-azido-]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine, 3-butyne-2-alcohol (16 μ L, 0.2mmol) replace 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-triazolyl)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 47, is replaced cyclopropyl acethlene, yield: 80.6% with 2-methyl-3-butyne-2-alcohol (20 μ L, 0.2mmol).
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-triazolyl)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 62.7% with (R)-2-methyl-3-butyne-2-alcohol (16 μ L, 0.2mmol).
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-triazolyl))]-5-[(methyl first sulfo group) amino]-N '-[(1S)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 70.3% with (S)-2-methyl-3-butyne-2-alcohol (16 μ L, 0.2mmol).
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)-1-phenylethyl] isophthaloyl amine
According to synthetic route 1, trinitride (the 2S making with reference to embodiment 1,3S)-1-benzyl-2-hydroxyl-3-azido-t-butyl carbamate (306mg, 1mmol) and propargyl alcohol (118 μ L, 2mmol) join in the THF of 4mL and the water of 1mL, after stirring, the anti-sepsis acid sodium (20mg that adds 0.1 equivalent, 0.1mmol), the cupric sulfate pentahydrate (13mg, 0.05mmol) of 0.05 equivalent.Reaction is counter spending the night under the condition of 50 ℃ of heating.Concentrated, add water (10mL), ethyl acetate extraction (10mL * 3), merges organic phase, with saturated common salt washing (10mL * 1), anhydrous sodium sulfate drying, filters, and the concentrated crude product 320mg that to obtain not purifiedly directly carries out next step reaction;
The crude product (36mg, 0.1mmol) that upper step is obtained is dissolved in the methylene dichloride of 1mL, adds the trifluoroacetic acid of 0.2mL, under room temperature, stirs 2h.The unhindered amina that obtains sloughing after Boc after concentrated directly carries out next step reaction;
Get (R)-3-(N-methyl methylsulfonyl) amino-5-N-(1-phenyl) ethyl carbamyl phenylformic acid (34mg; 0.09mmol) be dissolved in 1mL dry DMF, ice-water bath is cooling, adds successively EDCI (18mg; 0.9mmol); HOBt (12mg, 0.09mmol), DIPEA (76 μ L; 0.44mmol); stir after 5min, add the above-mentioned amine that is dissolved in 1mL DMF, allow reaction system naturally heat up and react 10min at 70 ℃ of microwave-assisted.Add 30mL ethyl acetate, organic layer is washed (10mL * 2) twice with saturated sodium bicarbonate, wash one time (10mL * 1), saturated common salt water washing one time (10mL * 1), anhydrous sodium sulfate drying, filters, concentrated, directly TLC chromatography obtains 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
Synthetic technology route is with reference to described in embodiment 51; just with 3-nitro-5-(N; N-dipropyl) carbamyl phenylformic acid (26mg; 0.09mmol) replace (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
Synthetic technology route is with reference to described in embodiment 51; just with 5-methyl-3-(N; N-dipropyl) carbamyl phenylformic acid (24mg; 0.09mmol) replace (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)-2-(methoxymethyl) pyrroles] isophthaloyl amine
Synthetic technology route is with reference to described in embodiment 51; just with 5-methyl-3-((R)-2-(methoxymethyl) pyrroles) formyl radical phenylformic acid (25mg; 0.09mmol) replace (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)-1-(4-fluorophenyl) ethyl] isophthaloyl amine
Synthetic technology route is with reference to described in embodiment 51; just with (R)-3-N-(1-(4-fluorophenyl) ethyl) carbamyl phenylformic acid (26mg; 0.09mmol) replace (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)-1-phenylethyl] isophthaloyl amine
Triazo-compound N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-azido-]-5-[(methyl first sulfo group) amino] compound N-[(1S in the synthetic method of-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine and embodiment 1, 2S)-1-benzyl-2-hydroxyl-3-azido-]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine synthetic method is identical, just with 5-(methyl methylsulfonyl) amino-3-((1R)-1-phenyl) ethyl aminocarbonyl phenylformic acid, replace 5-(methyl methylsulfonyl) amino-3-((1R)-1-(4-fluorophenyl) ethyl) aminocarbonyl phenylformic acid, obtain 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-]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine (28mg, 0.05mmol) replace compound N-[(1S, 2S)-1-benzyl-2-hydroxyl-3-azido-]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-(4-fluorophenyl) ethyl] isophthaloyl amine, with 1-pentyne (20 μ L, 0.2mmol) replace 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)-1-phenylethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 56, is replaced cyclopropyl acethlene, yield: 69.8% with 1-hexin (23 μ L, 0.2mmol).
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)-1-phenylethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 56, is replaced cyclopropyl acethlene, yield: 79.5% with (26 μ L, 0.2mmol).
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)-1-phenylethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 56, is replaced cyclopropyl acethlene, yield: 78.9% with 3-methyl isophthalic acid-butine (19 μ L, 0.2mmol).
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)-1-phenylethyl] isophthaloyl amine
Synthetic technology route is with reference to described in 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)-1-phenylethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 56, is replaced cyclopropyl acethlene, yield: 81.7% with tert-butyl acetylene (25 μ L, 0.2mmol).
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)-1-phenylethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 56, is replaced cyclopropyl acethlene, yield: 67.8% with 4-methyl-1-pentene alkynes (23 μ l, 0.2mmol).
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)-1-phenylethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 56, is replaced cyclopropyl acethlene, yield: 83.5% with 3-methyl isophthalic acid-hexin (28 μ l, 0.2mmol).
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)-1-phenylethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 56, is replaced cyclopropyl acethlene, yield: 86.2% with cyclopentyl acetylene (23 μ l, 0.2mmol).
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)-1-phenylethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 56, is replaced cyclopropyl acethlene, yield: 86.4% with 5-methyl isophthalic acid-hexin (25 μ l, 0.2mmol).
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)-1-phenylethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 56, is replaced cyclopropyl acethlene, yield: 93.6% with phenylacetylene (22 μ l, 0.2mmol).
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)-1-phenylethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 56, is replaced cyclopropyl acethlene, yield: 92.1% with 4-tert.-butylbenzene acetylene (34 μ l, 0.2mmol).
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)-1-phenylethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 56, is replaced cyclopropyl acethlene, yield: 62.3% with (R)-(+)-3-butyne-2-alcohol (16 μ l, 0.2mmol).
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)-1-phenylethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 56, is replaced cyclopropyl acethlene, yield: 52.1% with (S)-(+)-3-butyne-2-alcohol (16 μ L, 0.2mmol).
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)-1-phenylethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 56, is replaced cyclopropyl acethlene, yield: 78.8% with 1-hexin-3-alcohol (23 μ l, 0.2mmol).
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)-1-phenylethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 71.5% with 4-methyl-1-pentene alkynes-3-alcohol (21 μ l, 0.2mmol).
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)-1-phenylethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 82.1% with 1-octyne-3-alcohol (29 μ l, 0.2mmol).
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)-1-phenylethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 83.2% with 5-methyl isophthalic acid-hexin-3-alcohol (25 μ l, 0.2mmol).
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 group) ethyl-1,2,3-triazolyl)]-5-[(methyl first sulfo group) amino]-N '-[(1R)-1-phenylethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 10, is replaced cyclopropyl acethlene, yield: 88.2% with 1-(3-trifluoromethyl) phenoxy group-3-butyne-2-alcohol (23mg, 0.1mmol).
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)-1-phenylethyl] isophthaloyl amine
By trinitride H ((2S, 3R)-2-benzyl-4-azido--3-hydroxyl-1-tertbutyloxycarbonyl propylamine) (3.06g, 10mmol); phthalic imidine (1.59g, 12mmol), triphenylphosphine (4.71g; 20mmol) be dissolved in the THF that 60mL is dry; under the protection of nitrogen, in system, add azoformic acid isopropyl ester (3.6g, 20mmol), room temperature reaction 6h; concentrated; directly carry out column chromatography, obtain white solid I 4.03g, 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 1mL trifluoroacetic acid, under room temperature, reacts 2h.Concentrated, obtain J ((2S, 3R)-2-benzyl-3-phthalimidyl-4-azido--1-propylamine) crude product, not purifiedly directly enter next step reaction.
Get 5-(methyl methylsulfonyl) amino-3-((1R)-1-phenyl) ethyl aminocarbonyl phenylformic acid (413mg; 1.1mmol) be dissolved in 4mL dry DMF, ice-water bath is cooling, adds successively EDCI (210mg; 1.1mmol); HOBt (149mg, 1.1mmol), DIPEA (760 μ L; 4.4mmol); stir after 5min, add the J that is dissolved in 1mL DMF, allow reaction system naturally heat up and react 10min at 70 ℃ of microwave-assisted.Add 30mL ethyl 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, and concentrates to obtain crude product.Petrol ether/ethyl acetate=1/1-1/2 crosses post, obtain 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)-1-phenylethyl] isophthaloyl amine) (35mg, 0.05mmol) with 3-methyl isophthalic acid-acetylene (19 μ L, 0.2mmol) join in the THF of 800 μ L and the water of 200 μ L, after stirring, the anti-sepsis acid sodium (2mg that adds 0.2 equivalent, 0.01mmol), the cupric sulfate pentahydrate (1mg, 0.005mmol) of 0.1 equivalent.Reaction is reacted 12-24h under the condition of 50 ℃ of heating, directly by TLC chromatography, obtains intermediate triazole compounds.The intermediate obtaining is dissolved in the ethanol of 1mL, adds NH
2nH
2h
2o (20uL, 0.4mmol), reacts under the condition of 60 ℃ of heating and reacts 24h.Reaction solution is concentrated, directly by TLC chromatography, obtains end product L 9mg, yield: 28.6%.
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)-1-phenylethyl] isophthaloyl amine
Synthetic technology route, with reference to described in embodiment 75, is replaced 3-methyl isophthalic acid-acetylene, yield: 23.1% with tert-butyl acetylene (16mg, 0.2mmol).
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) acquisition of beta-secretase albumen:
Experiment adopts beta-secretase extracellular region protein, and 1-454 amino acid (hereinafter referred BACE1), is secretory protein, gene constructed in pFastBac by this albumen
tMin 1 carrier, C end adds 6 Histidines.By
(Invitrogen) baculovirus expression system obtains target protein.
First recombinant plasmid transformed is arrived to intestinal bacteria DH10Bac
tMin competent cell, wherein comprised baculovirus shuttle vectors, i.e. rod granule, picking contains pFastBac after transposition
tMthe recombinant clone of middle goal gene section, cultivates and extracting restructuring rod granule.By the Sf9 insect cell of restructuring rod granule transfection complete TNM-FH culture medium culturing, cultivate and within 3-5 days, gather in the crops afterwards the substratum that contains first-generation virus, continue transfection and obtain respectively the s-generation, third generation virus.The substratum that employing contains third generation virus infects Express
the High Five that serum free medium is cultivated
tMinsect cell, expresses target protein, collects the substratum that contains target protein after 72 hours, needs next step purifying.Level pad (20mM sodium phosphate (sodium phosphate) pH8.0 by the substratum that contains target protein (25-30mL) at 1L, 300mM NaCl, 10mM imidazoles (imidazole)) dialysed overnight in, centrifugal 15 minutes of 12000rpm, repeat once, collect supernatant liquor.By supernatant liquor loading to through metal ion-chelant chromatography column (the 1mL HiTrap of level pad balance
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, finally, the albumen obtaining through 12% polyacrylamide gel electrophoresis (SDS-PAGE) isolation identification purifying, purity is 90% left and right.
(2) determination of activity
DABCYL-Ser-Glu-Val-Asn-Leu-Asp-Ala-Glu-Phe-EDANS (Synpep is used in experiment, lower abbreviation BS) as substrate, survey the reaction of living carries out in 384 hole microwell plates, 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, at the multi-functional plate instrument Envision that reads
tM(PerkinElmer) in, detect fluorescent signal, excite with absorbing wavelength and be respectively 355nm and 460nm, record and calculate the increment of enzyme reaction initial stage unit time fluorescent signal, with this, represent enzyme reaction initial velocity, with testing compound, the inhibiting rate of beta-secretase activity is represented the activity of this compound, wherein, inhibiting rate (inhibition) calculates and sees formula 1.
υ in formula 1
compoundand υ
dMSOthe enzyme reaction initial velocity that representative contains compound and DMSO respectively.
If compound to be detected inhibiting rate when 20 μ g/mL is greater than 50%, more further dilutes 7-9 concentration, calculate IC
50, i.e. the concentration of the suppressed half compound of enzyme initial velocity.Positive inhibitor is compound OM99-2 (OM99-2 be take octapeptide [L-glutamic acid-OMR99-1] as basis, has replaced the compound of Leu-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
By the screening on molecular level, discovery part of compounds shows has good activity to beta-secretase, and for further research may have the cognitive function of improvement, the original new drug of simultaneously alleviating AD progression of disease provides valuable information.
Claims (10)
1. the hydroxyethyl triazole class compounds or aminoethyl triazole class compounds or its pharmacy acceptable salt that as following general formula I, represent:
Wherein:
R
2for
h, C
1-C
4straight or branched alkyl or nitro; Wherein, R
7for H, C
1-C
6straight or branched alkyl or C
3-C
6cycloalkyl; R
8for H, C
1-C
6straight or branched alkyl or C
3-C
6cycloalkyl;
R
3for phenyl;
W and V are CH;
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
6cycloalkyl, C
3-C
6methyl cycloalkyl, C
1-C
6carboxyl ester group, ethanoyl, N, N-dimethylaminomethyl, halogen,
or
wherein, the integer that n is 1-3, R
9for H, ethanoyl, phenyl, benzyl or α-acrinyl, R
10for C
1-C
6straight or branched alkyl, C
3-C
6phenoxymethyl or phenyl that cycloalkyl, trifluoromethyl replace;
Wherein, described phenyl is not necessarily by C
1-C
6straight or branched alkyl, halogen, methoxy substitution, described heteroaryl is for containing the heteroatomic six membered heteroaryl of N.
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 described compound is hydroxyethyl triazole class compounds:
R
1for
or
wherein, X is NH; Y is
r
6for H or C
1-C
6straight or branched alkyl;
R
2for
nitro or H; Wherein, R
7for H, C
1-C
6straight or branched alkyl or C
3-C
6cycloalkyl; R
8for H, C
1-C
6straight or branched alkyl or C
3-C
6cycloalkyl.
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 described compound is aminoethyl triazole class compounds:
R
1for
or
wherein, X is NH; Y is
r
6for H or C
1-C
6straight or branched alkyl;
R
2for
nitro or H; Wherein, R
7for H, C
1-C
6straight or branched alkyl or C
3-C
6cycloalkyl; R
8for H, C
1-C
6straight or branched alkyl or C
3-C
6cycloalkyl.
4. hydroxyethyl triazole class compounds according to claim 1 or aminoethyl triazole class compounds or its pharmacy acceptable salt, is characterized in that, one of described hydroxyethyl triazole class compounds or aminoethyl triazole class compounds are following compound:
5. the preparation method of hydroxyethyl triazole class compounds as described in claim 2, is characterized in that, the method is used following synthetic route 1,2 or 3:
Synthetic route 1:
Reactions steps is as follows:
A) take epoxy compounds A as starting raw material, the methyl alcohol of take under ammonium chloride exists with sodiumazide obtains compd B as solvent refluxing reacts open loop,
B) compd B is sloughed Boc protecting group and is obtained Compound C under acidic conditions,
C), under the condition that one or more compounds exist in EDCI, HOBt and DIPEA, Compound C further obtains Compound D with the phenylformic acid condensation that R1 and R2 replace,
D) the synthetic of 4-position replacement hydroxyethyl triazole compounds E be take mantoquita as catalyzer, and anti-sepsis acid sodium is reductive agent, makes Compound D under 50 ℃ of reactions, react 24-48 hour in THF/H2O mixed solvent, by silicagel column or thin plate layer analysis method, obtains;
Synthetic route 2:
Wherein, reactions steps a), b), c) the same, at reactions steps d) in:
5-position replaces the synthetic with Ru (PPh of hydroxyethyl triazole class compounds F
3)
2cl
2for catalyzer, take THF as solvent, make Compound D heating condition under with
reaction 12-24 hour, obtains by silicagel column or thin plate layer analysis method;
Or, synthetic route 3:
Wherein, reactions steps a), b), c) the same, at reactions steps d) in:
It is synthetic that 4,5-bis-replaces hydroxyethyl triazole class compounds G is alternatively by copper catalysis, and directly take toluene as solvent, make Compound D under the condition of heating with
reaction obtains.
6. the preparation method of aminoethyl triazole class compounds as described in claim 3, is characterized in that, the method is used following synthetic route:
Reactions steps is as follows:
A) take compound H as starting raw material, the THF of take under the existence of triphenyl phosphorus, azoformic acid isopropyl ester with phthalic diamide obtains Compound I in room temperature reaction as solvent,
B) Compound I is sloughed Boc protecting group and is obtained compound J under acidic conditions,
C) under the phenylformic acid condition that one or more compounds exist in EDCI, HOBt and DIPEA that compound J further replaces with R1 and R2, condensation obtains compound K,
D) the synthetic of 4-position replacement aminoethyl triazole class compounds L is to take mantoquita as catalyzer, and anti-sepsis acid sodium is reductive agent, makes compound K at THF/H
2in O mixed solvent, under 50 ℃ of reactions, react 24-48 hour, by silicagel column or thin plate layer analysis method, obtain.
7. according to the method described in claim 5 or 6, it is characterized in that, described mantoquita is cupric sulfate pentahydrate or cuprous iodide.
8. according to the method described in claim 5 or 6, it is characterized in that step b) described in acidic conditions be the condition at trifluoroacetic acid or hydrochloric acid.
Hydroxyethyl triazole class compounds claimed in claim 1 or aminoethyl triazole class compounds or its pharmacy acceptable salt for the preparation of prevention, delay or treat the purposes in the medicine of the disease of the deposition initiation of A β.
10. purposes according to claim 9, the disease that the wherein said deposition by A β causes is presenile dementia.
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Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1447789A (en) * | 2000-06-30 | 2003-10-08 | 艾兰制药公司 | Compounds to treat alzheimer's disease |
| 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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2010
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Patent Citations (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN1447789A (en) * | 2000-06-30 | 2003-10-08 | 艾兰制药公司 | Compounds to treat alzheimer's disease |
| 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 |
Non-Patent Citations (2)
| Title |
|---|
| β-分泌酶抑制剂的研究进展;肖坤等;《中国药物化学杂志》;20060831;第16卷(第4期);第246-252页 * |
| 肖坤等.β-分泌酶抑制剂的研究进展.《中国药物化学杂志》.2006,第16卷(第4期),第246-252页. |
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