CN105152977B - D D-pHPG derivatives and its preparation method and application - Google Patents

D D-pHPG derivatives and its preparation method and application Download PDF

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CN105152977B
CN105152977B CN201510641211.8A CN201510641211A CN105152977B CN 105152977 B CN105152977 B CN 105152977B CN 201510641211 A CN201510641211 A CN 201510641211A CN 105152977 B CN105152977 B CN 105152977B
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bases
phenyl
acetylphenyls
fonnylphenyls
phpg
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CN105152977A (en
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杨大成
曹园
范莉
杨龙
刘晓华
蒋佳
黄亚兰
叶晶晶
吴晓霞
曹丽君
周围
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Southwest University
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Abstract

The invention discloses a kind of D D-pHPGs derivative, with following structural formula, the present invention is with D D-pHPGs as parent, its amino and carboxyl are reasonably modified, and be connected with fragrant ring-like hydrophobic grouping by a connexon on phenolic hydroxyl group, construct the novel D D-pHPG derivatives of a class formation, and therefrom filtered out with the compound for promoting the secretion activities of GLP 1 and/or Nav1.7 inhibitory activity, these compounds process for production thereof are simple, can be used for preparing the secernents of GLP 1 and/or Nav1.7 inhibitor, there is potential application prospect in Remedies for diabetes and/or neurogenic pain medicine field.

Description

D-pHPG derivative and its preparation method and application
Technical field
The invention belongs to technical field of medicine synthesis, it is related to a class noval chemical compound, its preparation method and its in pharmacy Using.
Background technology
D-pHPG (D-PHPG) is currently used primarily in beta-lactam hemizygous as a kind of medicine intermediate Into the production of antibiotic, such as amoxycillin (Amoxicillin), cephalo hydroxyl benzyl (Ou Yi), cephalo chlorobenzene (pioneer IV), Cefoperazone, cephalo Luo Qi, SKF-60771, Cefaclor, Cefradine (Ancef I), cefatrizine, Cefalexin etc. are wide Spectrum antibiotic it is synthetically produced in, D-pHPG is essential side-chain acid.But both at home and abroad to D- para hydroxybenzenes The research of glycine derivative is less at present.
The content of the invention
In view of this, it is an object of the invention to D-pHPG as parent, by it is carried out protection and Modification, the novel D-pHPG derivative of one class formation of synthesis, then therefrom filter out the target with pharmacological activity Molecule.
Through research, the present invention provides following technical scheme：
1.D- D-pHPG derivatives, with following structural formula：
R1It is methyl, ethyl, n-propyl or normal-butyl, Y is O, and Ar is 3- Fonnylphenyls, 2- Fonnylphenyls, 4- first Aminosulfonylphenyl, 4- methoxycarbonyl groups phenyl, 4- (2- oxo -2- methoxyl groups) ethylphenyl, 4- (3- oxo -3- methoxyl groups) propylbenzene Base, 4- propionylphenyls, 4- acetylphenyls, 2- acetylphenyls, 3- acetylphenyls, 5- formoxyl -2- methoxyphenyls, 4- formoxyl -2- methoxyphenyls, 4- acetylamino phenyls, phenyl, naphthalene -2- bases or 2- oxo -2H- chromene -4- bases；
Or, R1It is methyl, ethyl, n-propyl or normal-butyl, Y is S, and Ar is benzo [d] oxazole -2- bases, 1H- benzos [d] imidazoles -2- bases, 5- amino -1,3,4- thiadiazoles -2- bases or 4- hydroxyl -6- aminopyrimidine -2- bases；
Or, R1It is methyl, ethyl, n-propyl or normal-butyl, Y is SO2, Ar is 1H- benzos [d] imidazoles -2- bases；
Or, R1It is hydrogen, Y is O, and Ar is 3- Fonnylphenyls, 2- Fonnylphenyls, 4- Fonnylphenyls, 4- carboxyl benzene Base, 4- carboxymethyls phenyl, 4- carboxyethyl phenyls, 4- propionylphenyls, 4- acetylphenyls, 2- acetylphenyls, 3- acetyl group Phenyl, 5- formoxyl -2- methoxyphenyls, 4- formoxyl -2- methoxyphenyls, 4- acetylamino phenyls, phenyl, naphthalene -2- bases Or 2- oxo -2H- chromene -4- bases；
Or, R1It is hydrogen, Y is S, and Ar is benzo [d] oxazole -2- bases or 1H- benzos [d] imidazoles -2- bases.
Preferably, R1It is methyl, Y is O, and Ar is 3- Fonnylphenyls, 2- Fonnylphenyls, 4- methoxycarbonyl groups phenyl, 4- Propionylphenyl, 4- acetylphenyls, 2- acetylphenyls, 3- acetylphenyls, 5- formoxyl -2- methoxyphenyls, 4- first Acyl group -2- methoxyphenyls, phenyl or 2- oxo -2H- chromene -4- bases；
Or, R1It is ethyl, Y is O, and Ar is 2- Fonnylphenyls, 2- acetylphenyls, 3- acetylphenyls or phenyl；
Or, R1It is n-propyl, Y is O, and Ar is 4- acetylphenyls, phenyl or naphthalene -2- bases；
Or, R1It is normal-butyl, Y is O, and Ar is 2- Fonnylphenyls or phenyl；
Or, R1It is methyl or ethyl, Y is S, and Ar is benzo [d] oxazole -2- bases, 1H- benzos [d] imidazoles -2- bases or 4- Hydroxyl -6- aminopyrimidine -2- bases；
Or, R1It is n-propyl, Y is S, and Ar is 1H- benzos [d] imidazoles -2- bases, 5- amido-1,3,4-thiadiazoles -2- bases Or 4- hydroxyl -6- aminopyrimidine -2- bases；
Or, R1It is normal-butyl, Y is S, and Ar is 1H- benzos [d] imidazoles -2- bases or 4- hydroxyl -6- aminopyrimidine -2- bases；
Or, R1It is methyl, ethyl or n-propyl, Y is SO2, Ar is 1H- benzos [d] imidazoles -2- bases；
Or, R1It is hydrogen, Y is O, and Ar is 4- acetylamino phenyls, phenyl or naphthalene -2- bases；
Or, R1It is hydrogen, Y is S, and Ar is benzo [d] oxazole -2- bases.
It is furthermore preferred that R1It is methyl, Y is O, and Ar is 4- acetylphenyls or 2- acetylphenyls；
Or, R1It is ethyl or normal-butyl, Y is O, and Ar is 2- Fonnylphenyls or phenyl；
Or, R1It is n-propyl, Y is O, and Ar is phenyl or naphthalene -2- bases；
Or, R1It is methyl, Y is S, and Ar is 1H- benzos [d] imidazoles -2- bases or 4- hydroxyl -6- aminopyrimidine -2- bases；
Or, R1Be ethyl, Y is S, Ar be benzo [d] oxazole -2- bases, 1H- benzos [d] imidazoles -2- bases or 4- hydroxyls - 6- aminopyrimidine -2- bases；
Or, R1It is methyl or ethyl, Y is SO2, Ar is 1H- benzos [d] imidazoles -2- bases.
The preparation method of 2.D- D-pHPG derivatives, step is as follows：
1) D-pHPG and benzene methoxy carbonyl acyl succinimide Z-OSu are reacted in the middle of generation under base catalysis Body IM1, IM1 again with alcohol R1OH reacts generation intermediate compound I M2 under thionyl chloride effect；
2) intermediate compound I M2 and 1,3- dibromopropanes are reacted into generation intermediate compound I M3 under base catalysis；
3) intermediate compound I M3 and aromatic compound A are reacted into generation D-pHPG derivative under base catalysis TM1；
4) it is that mCPBA reactions generate D- to hydroxyl by D-pHPG derivative TM1-18 and metachloroperbenzoic acid Base phenylglycine derivatives TM2；
5) generation D-pHPG is acidified after D-pHPG derivative TM1 is hydrolyzed under base catalysis Derivative TM3；
Alcohol R1In OH, intermediate compound I M2 and IM3, R1It is methyl, ethyl, n-propyl or normal-butyl；
In aromatic compound A and D-pHPG derivative TM1, R1It is methyl, ethyl, n-propyl or positive fourth Base, Y is O, Ar be 3- Fonnylphenyls, 2- Fonnylphenyls, 4- Fonnylphenyls, 4- methoxycarbonyl groups phenyl, 4- (2- oxos- 2- methoxyl groups) ethylphenyl, 4- (3- oxo -3- methoxyl groups) propyl group phenyl, 4- propionylphenyls, 4- acetylphenyls, 2- second Aminosulfonylphenyl, 3- acetylphenyls, 5- formoxyl -2- methoxyphenyls, 4- formoxyl -2- methoxyphenyls, 4- acetylaminos Phenyl, phenyl, naphthalene -2- bases or 2- oxo -2H- chromene -4- bases；Or, R1It is methyl, ethyl, n-propyl or normal-butyl, Y is S, Ar be benzo [d] oxazole -2- bases, 1H- benzos [d] imidazoles -2- bases, 5- amido-1,3,4-thiadiazoles -2- bases or 4- hydroxyls - 6- aminopyrimidine -2- bases；
In D-pHPG derivative TM2, R1It is methyl, ethyl, n-propyl or normal-butyl；
In D-pHPG derivative TM3, R1It is hydrogen, Y is O, and Ar is 3- Fonnylphenyls, 2- formoxyl benzene Base, 4- Fonnylphenyls, 4- carboxyl phenyls, 4- carboxymethyls phenyl, 4- carboxyethyl phenyls, 4- propionylphenyls, 4- acetylbenzenes Base, 2- acetylphenyls, 3- acetylphenyls, 5- formoxyl -2- methoxyphenyls, 4- formoxyl -2- methoxyphenyls, 4- second Amido phenyl, phenyl, naphthalene -2- bases or 2- oxo -2H- chromene -4- bases；Or, R1It is hydrogen, Y is S, and Ar is benzo [d] Evil Azoles -2- bases or 1H- benzos [d] imidazoles -2- bases.
Preferably, step 1) it is in boiling by D-pHPG and benzene methoxy carbonyl acyl succinimide Z-OSu In mixed solvent, potassium carbonate catalysis, 15-35 DEG C, react under the conditions of pH8-9 generation intermediate compound I M1, IM1 again with alcohol R1OH is in chlorine Change the lower heating response generation intermediate compound I M2 of sulfoxide effect.
Preferably, step 2) be by intermediate compound I M2 and 1,3- dibromopropane in acetonitrile, potassium carbonate catalysis, 45-55 DEG C of bar Generation intermediate compound I M3 is reacted under part.
Preferably, step 3) be by intermediate compound I M3 and aromatic compound A in DMF, potassium carbonate urges Change, generation D-pHPG derivative TM1 is reacted under the conditions of 15-35 DEG C.
Preferably, step 4) be by D-pHPG derivative TM1-18 and mCPBA in dichloromethane, 15- Generation D-pHPG derivative TM2 is reacted under the conditions of 35 DEG C.
Preferably, step 5) be by D-pHPG derivative TM1 in tetrahydrofuran, lithium hydroxide catalysis, Under the conditions of 15-35 DEG C generation D-pHPG derivative TM3 is acidified after hydrolysis with hydrochloric acid.
3.D- D-pHPGs derivative is preparing glucagon-like-peptide-1 (glucagon-like peptide 1, GLP-1) application in secernent, the D-pHPG derivative has following structural formula：
R1It is methyl, Y is O, and Ar is 3- Fonnylphenyls, 2- Fonnylphenyls, 2- acetylphenyls, 4- formoxyls -2- Methoxyphenyl, 4- acetylamino phenyls, phenyl or 2- oxo -2H- chromene -4- bases；
Or, R1It is ethyl, Y is O, and Ar is 3- Fonnylphenyls, 2- Fonnylphenyls, 4- Fonnylphenyls, 4- methoxies Carbonyl phenyl, 4- (2- oxo -2- methoxyl groups) ethylphenyl, 4- (3- oxo -3- methoxyl groups) propyl group phenyl, 4- acetylbenzenes Base, 2- acetylphenyls, 3- acetylphenyls, 4- acetylamino phenyls, phenyl, naphthalene -2- bases or 2- oxo -2H- chromenes -4- Base；
Or, R1It is n-propyl, Y is O, and Ar is 3- Fonnylphenyls, 2- Fonnylphenyls, 4- Fonnylphenyls, 4- (3- Oxo -3- methoxyl groups) propyl group phenyl, 4- acetylphenyls, 3- acetylphenyls, 5- formoxyl -2- methoxyphenyls, 4- formyls Base -2- methoxyphenyls, phenyl, naphthalene -2- bases or 2- oxo -2H- chromene -4- bases；
Or, R1It is normal-butyl, Y is O, and Ar is 2- Fonnylphenyls, 4- Fonnylphenyls, 4- (3- oxo -3- methoxies Base) propyl group phenyl, 2- acetylphenyls, 5- formoxyl -2- methoxyphenyls, 4- formoxyl -2- methoxyphenyls, 4- acetyl ammonia Base phenyl, phenyl or 2- oxo -2H- chromene -4- bases；
Or, R1It is methyl, Y is S, and Ar is benzo [d] oxazole -2- bases；
Or, R1It is ethyl or n-propyl, Y is S, and Ar is benzo [d] oxazole -2- bases or 1H- benzos [d] imidazoles -2- bases；
Or, R1It is methyl, n-propyl or normal-butyl, Y is SO2, Ar is 1H- benzos [d] imidazoles -2- bases；
Or, R1It is hydrogen, Y is O, and Ar is 3- Fonnylphenyls, 2- Fonnylphenyls, 4- Fonnylphenyls, 4- carboxyl benzene Base, 4- carboxymethyls phenyl, 4- propionylphenyls, 4- acetylphenyls, 2- acetylphenyls, 3- acetylphenyls, 5- formoxyls- 2- methoxyphenyls, 4- acetylamino phenyls, phenyl, naphthalene -2- bases or 2- oxo -2H- chromene -4- bases；
Or, R1It is hydrogen, Y is S, and Ar is benzo [d] oxazole -2- bases or 1H- benzos [d] imidazoles -2- bases.
Preferably, in the structural formula of the D-pHPG derivative,
R1It is methyl, Y is O, and Ar is 2- acetylphenyls, phenyl or 2- oxo -2H- chromene -4- bases；
Or, R1It is ethyl or normal-butyl, Y is O, and Ar is 2- Fonnylphenyls or phenyl；
Or, R1It is n-propyl, Y is O, and Ar is phenyl or naphthalene -2- bases；
Or, R1It is ethyl, Y is S, and Ar is benzo [d] oxazole -2- bases；
Or, R1It is n-propyl, Y is SO2, Ar is 1H- benzos [d] imidazoles -2- bases；
Or, R1It is hydrogen, Y is O, and Ar is phenyl or naphthalene -2- bases；
Or, R1It is hydrogen, Y is S, and Ar is benzo [d] oxazole -2- bases.
It is furthermore preferred that in the structural formula of the D-pHPG derivative,
R1It is ethyl or normal-butyl, Y is O, and Ar is 2- Fonnylphenyls or phenyl；
Or, R1It is n-propyl, Y is O, and Ar is phenyl or naphthalene -2- bases；
Or, R1It is ethyl, Y is S, and Ar is benzo [d] oxazole -2- bases.
Application of the 4.D- D-pHPGs derivative in Voltage-gated sodium channels Nav1.7 inhibitor is prepared, The D-pHPG derivative has following structural formula：
R1It is methyl, Y is O, and Ar is 3- Fonnylphenyls, 2- Fonnylphenyls, 4- Fonnylphenyls, 4- methoxycarbonyl phenyls Base, 4- (2- oxo -2- methoxyl groups) ethylphenyl, 4- (3- oxo -3- methoxyl groups) propyl group phenyl, 4- propionylphenyls, 4- second Aminosulfonylphenyl, 2- acetylphenyls, 3- acetylphenyls, 5- formoxyl -2- methoxyphenyls, 4- formoxyl -2- methoxybenzenes Base, phenyl, naphthalene -2- bases or 2- oxo -2H- chromene -4- bases；
Or, R1It is ethyl, Y is O, and Ar is 3- Fonnylphenyls, 4- acetylphenyls, 2- acetylphenyls, 3- acetyl Base phenyl or phenyl；
Or, R1It is n-propyl, Y is O, and Ar is 2- Fonnylphenyls, 4- acetylphenyls, 2- acetylphenyls, 5- first Acyl group -2- methoxyphenyls, 4- formoxyl -2- methoxyphenyls, 4- acetylamino phenyls or 2- oxo -2H- chromene -4- bases；
Or, R1It is normal-butyl, Y is O, and Ar is 2- Fonnylphenyls, 4- Fonnylphenyls, 4- methoxycarbonyl groups phenyl, 4- Propionylphenyl, 2- acetylphenyls, 3- acetylphenyls, 4- acetylamino phenyls, naphthalene -2- bases or 2- oxo -2H- chromenes - 4- bases；
Or, R1It is methyl, ethyl, n-propyl or normal-butyl, Y is S, and Ar is benzo [d] oxazole -2- bases, 1H- benzos [d] imidazoles -2- bases, 5- amino -1,3,4- thiadiazoles -2- bases or 4- hydroxyl -6- aminopyrimidine -2- bases；
Or, R1It is methyl, ethyl, n-propyl or normal-butyl, Y is SO2, Ar is 1H- benzos [d] imidazoles -2- bases；
Or, R1It is hydrogen, Y is O, and Ar is 4- carboxymethyls phenyl, 4- carboxyethyl phenyls, 4- acetylphenyls, 2- acetyl group Phenyl, 4- formoxyl -2- methoxyphenyls, 4- acetylamino phenyls or naphthalene -2- bases；
Or, R1It is hydrogen, Y is S, and Ar is benzo [d] oxazole -2- bases or 1H- benzos [d] imidazoles -2- bases.
Preferably, in the structural formula of the D-pHPG derivative,
R1It is methyl, Y is O, and Ar is 3- Fonnylphenyls, 2- Fonnylphenyls, 4- methoxycarbonyl groups phenyl, 4- propiono benzene Base, 4- acetylphenyls, 2- acetylphenyls, 3- acetylphenyls, 5- formoxyl -2- methoxyphenyls, 4- formoxyl -2- first Phenyl, phenyl or 2- oxo -2H- chromene -4- bases；
Or, R1It is ethyl, Y is O, and Ar is 2- acetylphenyls, 3- acetylphenyls or phenyl；
Or, R1It is n-propyl, Y is O, and Ar is 4- acetylphenyls；
Or, R1Be methyl, Y is S, Ar be benzo [d] oxazole -2- bases, 1H- benzos [d] imidazoles -2- bases or 4- hydroxyls - 6- aminopyrimidine -2- bases；
Or, R1It is ethyl or normal-butyl, Y is S, and Ar is that 1H- benzos [d] imidazoles -2- bases or 4- hydroxyl -6- amino are phonetic Pyridine -2- bases；
Or, R1It is n-propyl, Y is S, and Ar is 1H- benzos [d] imidazoles -2- bases, 5- amido-1,3,4-thiadiazoles -2- bases Or 4- hydroxyl -6- aminopyrimidine -2- bases；
Or, R1It is methyl, ethyl or n-propyl, Y is SO2, Ar is 1H- benzos [d] imidazoles -2- bases；
Or, R1It is hydrogen, Y is O, and Ar is 4- acetylamino phenyls.
It is furthermore preferred that in the structural formula of the D-pHPG derivative,
R1It is methyl, Y is O, and Ar is 4- acetylphenyls or 2- acetylphenyls；
Or, R1Be methyl or ethyl, Y is S, Ar be 1H- benzos [d] imidazoles -2- bases or 4- hydroxyl -6- aminopyrimidines - 2- bases；
Or, R1It is methyl or ethyl, Y is SO2, Ar is 1H- benzos [d] imidazoles -2- bases.
The beneficial effects of the present invention are：The present invention enters with D-pHPG as parent to its amino and carboxyl The rational modification of row, and be connected with fragrant ring-like hydrophobic grouping by a connexon (linker) on phenolic hydroxyl group, construct The novel D-pHPG derivative of one class formation, and therefrom filtered out with promote GLP-1 secretion activities and/or The compound of Nav1.7 inhibitory activity, these compounds process for production thereof are simple, can be used for preparing GLP-1 secernents and/ Or Nav1.7 inhibitor, there is potential application in Remedies for diabetes and/or neurogenic pain medicine field Prospect.
Specific embodiment
In order that the purpose of the present invention, technical scheme and beneficial effect are clearer, below will be to preferred reality of the invention Example is applied to be described in detail.
The synthesis of embodiment 1 intermediate compound I M1 and IM2
SM 83.55g (499.84mmol) and 2mol/L K is added in 2L round-bottomed flasks2CO3Aqueous solution 300mL, ice bath The lower stirring and dissolving of cooling, adds the acetone soln 200mL of Z-OSu 130.11g (522.07mmol), uses 2mol/L K2CO3Water Solution adjusts pH=8-9, and (15-35 DEG C) stirring reaction under environment temperature keeps pH constant, thin-layered chromatography in course of reaction (TLC) reaction process is monitored.After reaction terminates, 3mol/L hydrochloric acid regulation pH=7, revolving removes acetone, saturation K2CO3The aqueous solution Regulation pH=9, adds ethyl acetate (EtOAc) extraction (2 × 150mL), water phase ice bath cooling, concentrated hydrochloric acid to adjust pH=3-4, greatly Amount solid is separated out, and adds EtOAc extractions (3 × 250mL), organic phase is collected and merge, successively with saturated sodium-chloride water solution (3 × 200mL), water (3 × 200mL) washing, anhydrous Na2SO4Dry, suction filtration, filtrate revolving obtains final product intermediate compound I M1, yield 95%.
Appropriate alcohol R is added under ice bath in the round-bottomed flask of suitable size1OH, is slowly added dropwise appropriate SOCl2, activation 30min, removes ice bath, adds metering IM1, and heating response in oil bath, TLC monitoring reaction process are moved into after stirring.Reaction knot Shu Hou, vacuum rotary steam removes solvent, plus appropriate 5wt%NaHCO3The aqueous solution is stirred, then adds appropriate EtOAc dissolvings, layering to collect Organic phase, water is extracted 1 time with EtOAc, merges organic phase, plus appropriate saturated sodium-chloride water solution, water-soluble with saturated lemon Liquid adjusts pH=5-6, and layering, organic phase uses saturated sodium-chloride water solution and water washing, anhydrous Na successively2SO4Dry, suction filtration, filter Liquid is rotated, and obtains final product intermediate compound I M2.
The intermediate compound I M2 generated datas of table one
IM1 (R) -2- (((benzyloxy) carbonyl) amino) -2- (4- hydroxy phenyls) acetic acid：White solid；m.p.:140- 141℃；1H NMR(300MHz,DMSO-d6)δ:5.01(s,2H,PhCH2-), 5.04 (s, 1H, * CH), 6.71 (d, 2H, J= 8.4Hz, Ar-H), 7.19 (d, 2H, J=7.8Hz, Ar-H), 7.35 (s, 5H, Ar-H), 7.93 (d, 1H, J=7.8Hz, CONH),9.47(s,1H,-OH),12.60(s,1H,-COOH).
IM2-a (R)-2-(((benzyloxy) carbonyl) amino)-2- (4- hydroxy phenyls) methyl acetate：White solid；m.p.: 125-127℃；1H NMR(300MHz,DMSO-d6)δ:3.60(s,3H,-CH3),5.04(s,2H,PhCH2-),5.12(d,1H, J=7.8Hz, * CH), 6.72 (d, 2H, J=8.4Hz, Ar-H), 7.18 (d, 2H, J=8.4Hz, Ar-H), 7.31-7.34 (m, 5H, Ar-H), 8.14 (d, 2H, J=7.8Hz, CONH)
IM2-b (R)-2-(((benzyloxy) carbonyl) amino)-2- (4- hydroxy phenyls) ethyl acetate：White solid；m.p.: 131-133℃；1H NMR(300MHz,DMSO-d6)δ:1.10 (t, 3H, J=7.2Hz ,-CH3), 4.06 (m, 2H, J= 7.2Hz,-CH2-),5.04(s,2H,PhCH2-), 5.07 (d, 1H, J=7.8Hz, * CH), 7.71 (d, 2H, J=8.1Hz, Ar- H), 7.17 (d, 2H, J=8.1Hz, Ar-H), 7.35 (s, 5H, Ar-H), 8.09 (d, 1H, J=7.5Hz, CONH), 9.52 (s, 1H,-OH).
IM2-c (R)-2-(((benzyloxy) carbonyl) amino)-2- (4- hydroxy phenyls) propyl acetate：White solid；m.p.: 125-127℃；1H NMR(300MHz,DMSO-d6)δ:0.75 (t, 3H, J=7.5Hz ,-CH3),1.45-1.52(m,2H,- CH2-), 3.97 (t, 2H, J=6.0Hz ,-OCH2),5.04(s,2H,PhCH2-), 5.08 (d, 1H, J=7.8Hz, * CH), 6.71 (d, 2H, J=7.8Hz, Ar-H), 7.18 (d, 2H, J=7.8Hz, Ar-H), 7.35 (s, 5H, Ar-H), 8.11 (d, 1H, J= 7.5Hz,CONH).
IM2-d (R)-2-(((benzyloxy) carbonyl) amino)-2- (4- hydroxy phenyls) butyl acetate：White solid；m.p.: 131-133℃；1H NMR(300MHz,CDCl3)δ:0.86 (t, 3H, J=7.2Hz ,-CH3),1.25(m,2H,-CH2-),1.55 (t, 2H, J=6.3Hz ,-CH2-), 4.13 (d, 2H, J=5.4Hz ,-OCH2), 5.10 (d, 2H, J=2.4Hz, PhCH2-), 5.85 (d, 1H, J=6.6Hz, * CH), 6.76 (d, 2H, J=7.8Hz, Ar-H), 7.21 (d, 2H, J=7.8Hz, Ar-H), 7.35(s,5H,ArH).
The synthesis of the intermediate compound I M3 of embodiment 2
Appropriate IM2, acetonitrile, finely ground anhydrous K are added in the round-bottomed flask of suitable size2CO3, stir, add 1,3- Dibromopropane (IM2:K2CO3:1,3- dibromopropanes mol ratio is 1:4:6), 50 DEG C of oil bath heatings, TLC monitoring reaction process.Instead After should terminating, suction filtration, filtrate revolving obtains pale tan oil, silica gel column chromatography, eluent concentrated by rotary evaporation, natural cooling crystallization, Suction filtration, vacuum drying, obtains final product intermediate compound I M3.
The intermediate compound I M3 generated datas of table two
IM3-a (R) -2- (((benzyloxy) carbonyl) amino) -2- (4- (3- bromines propoxyl group) phenyl) methyl acetate：White is solid Body；m.p.:84-85℃；1H NMR(600MHz,DMSO-d6)δ:2.21-2.25(m,2H,-CH2-),3.61(s,3H,OCH3), 3.66 (t, 2H, J=6.6Hz ,-CH2), Br 4.07 (t, 2H, J=6.0Hz ,-OCH2),5.06(s,2H,PhCH2),5.21(d, 1H, J=7.2Hz, * CH), 6.93 (d, 2H, J=8.4Hz, Ar-H), 7.30-7.37 (m, 7H, Ar-H), 8.22 (d, 1H, J= 7.8Hz,CONH).
IM3-b (R) -2- (((benzyloxy) carbonyl) amino) -2- (4- (3- bromines propoxyl group) phenyl) ethyl acetate：White is solid Body；m.p.:89-90℃；1H NMR(300MHz,DMSO-d6)δ:1.22 (t, 3H, J=6.3Hz ,-CH3),2.33-2.34(m, 2H,-CH2-), 3.61 (t, 2H, J=6.0Hz ,-CH2), Br 4.11 (t, 2H, J=5.4Hz ,-OCH2), 4.21 (t, 2H, J= 9.9Hz,-OCH2),5.10(s,2H,PhCH2-), 5.30 (d, 1H, J=7.2Hz, * CH), 6.89 (d, 2H, J=6.9Hz, Ar- H),7.31(m,7H,Ar-H),8.03(s,1H,CONH).
IM3-c (R) -2- (((benzyloxy) carbonyl) amino) -2- (4- (3- bromines propoxyl group) phenyl) propyl acetate：White is solid Body；m.p.:94-95℃；1H NMR(600MHz,CDCl3)δ:0.83 (t, 3H, J=7.2Hz, CH3),1.56-1.61(m,2H,- CH2-),2.29-2.33(m,2H,-CH2-), 3.59 (t, 2H, J=6.0Hz ,-CH2Br),4.05-4.10(m,4H,2-OCH2), 5.09 (q, 2H, J=12.6Hz, 31.2Hz, PhCH2-), 5.30 (d, 1H, J=7.2Hz, * CH), 5.82 (d, 1H, J= 6.6Hz, CONH), 6.88 (d, 2H, J=8.4Hz, Ar-H), 7.28-7.37 (m, 7H, Ar-H)
IM3-d (R) -2- (((benzyloxy) carbonyl) amino) -2- (4- (3- bromines propoxyl group) phenyl) butyl acetate：White is solid Body；m.p.:121-123℃；1H NMR(300MHz,DMSO-d6)δ:0.86 (t, 3H, J=7.2Hz, CH3),1.24-1.26(m, 2H,-CH2-),1.52-1.59(m,2H,-CH2-),2.27-2.35(m,2H,-CH2-), 3.60 (t, 2H, J=6.3Hz ,- CH2Br),4.07-4.13(m,4H,2-OCH2), 5.07 (q, 2H, J=12.3Hz, 18.9Hz, PhCH2-), 5.29 (d, 1H, J= 6.9Hz, * CH), 5.81 (d, 1H, J=6.9Hz, CONH), 6.88 (d, 2H, J=8.4Hz, Ar-H), 7.26-7.34 (m, 7H, Ar-H).
The synthesis of the compound TM1 of embodiment 3
Aromatic compound A and 5-15mL DMF (DMF) are added in round-bottomed flask, after stirring and dissolving, Add powdery K2CO3, IM3 is added after stirring 30 minutes, (15-35 DEG C) stirring reaction under environment temperature, TLC monitoring reaction process. After reaction terminates, pour into frozen water, organic phase, washing, anhydrous Na are collected in EtOAc extractions2SO4Dry, suction filtration, filtrate decompression rotation Inspissation contracts, and silica gel column chromatography obtains final product purpose compound TM1.
The compound TM1 generated datas of table three
TM1-1a (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (3- formvlphenoxvs) propoxyl group) phenyl) acetic acid Methyl esters：White solid；m.p.:87-88℃；1H NMR(300MHz,CDCl3)δ:9.97(1H,s,CHO),7.17-7.46(11H, M, Ar-H), 6.89 (2H, d, J=8.4Hz, Ar-H), 5.77 (1H, d, J=6.3Hz, NH), 5.30 (1H, d, J=6.3Hz, * ), CH 5.09 (2H, d, J=4.8Hz, PhCH2-),4.14-4.22(4H,m,-OCH2),3.71(3H,s,OCH3),2.24-2.32 (2H,m,-CH2-)；13C NMR(75MHz,CDCl3)δ:191.7,171.1,159.0,158.6,154.9,137.3,135.7, 129.7,128.4,128.1,128.0,127.8,127.7,123.2,121.4,114.4,112.3,66.7,64.1,63.8, 56.9,52.4,28.6；HRMS:C27H27NO7[M+Na]+Calculated value 500.1680, measured value 500.1683.
TM1-1b (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (3- formvlphenoxvs) propoxyl group) phenyl) acetic acid Ethyl ester：White solid；m.p.:72-74℃；1H NMR(300MHz,CDCl3)δ:9.97(1H,s,CHO),7.46-7.27(11H, M, Ar-H), 6.98 (1H, d, J=8.4Hz, Ar-H), 5.81 (1H, d, J=7.2Hz, NH), 5.29 (1H, d, J=6.9Hz, * CH),5.14-5.04(2H,m,PhCH2-),4.24-4.08(6H,m,-OCH2),2.30-2.26(2H,m,-CH2-),1.20 (3H, t, d=7.2Hz, CH3)；13C NMR(151MHz,CDCl3)δ:192.10,171.07,159.55,159.05,155.45, 137.98,136.35,130.17,129.20,128.60,128.49,128.22,123.59,121.92,114.98,113.08, 67.14,64.81,64.42,61.91,57.56,29.27,14.10；HRMS:C28H29NO7[M+H]+Calculated value 492.2017, it is real Measured value 492.2020.
TM1-1c (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (3- formvlphenoxvs) propoxyl group) phenyl) acetic acid Propyl ester：White solid；m.p.:55-56℃；1H NMR(300MHz,CDCl3)δ:9.97(1H,s,CHO),7.34-7.26(11H, M, Ar-H), 6.88 (2H, d, J=7.8Hz, Ar-H), 5.81 (1H, d, J=6.3Hz, NH), 5.29 (1H, d, J=6.9Hz, * CH),5.14-5.03(2H,m,PhCH2-), 4.22 (2H, t, J=5.4Hz ,-OCH2-), 4.15 (2H, t, J=5.7Hz ,- OCH2-),4.10-4.04(2H,m,-OCH2-),2.30-2.26(2H,m,-CH2-),1.62-1.55(2H,m,-CH2-),0.82 (3H, t, J=7.2Hz, CH3)；13C NMR(75MHz,CDCl3)δ:192.26,171.17,159.45,158.95,155.41, 137.84,136.24,130.17,129.16,128.61,128.46,128.28,128.25,123.69,121.97,114.85, 112.81,67.43,67.12,64.65,64.27,57.48,29.17,21.87,10.25；HRMS:C29H31NO7[M+Na]+Meter Calculation value 528.1993, measured value 528.2002.
TM1-1d (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (3- formvlphenoxvs) propoxyl group) phenyl) acetic acid Butyl ester：White solid；m.p.:61-63℃；1H NMR(300MHz,CDCl3)δ:9.97(1H,s,CHO),7.46-7.17(11H, M, Ar-H), 6.98 (1H, d, J=8.1Hz, Ar-H), 5.81 (1H, d, J=6.6Hz, NH), 5.29 (1H, d, J=6.9Hz, * CH),5.14-5.03(2H,m,PhCH2-), 4.22 (2H, t, J=5.7Hz ,-OCH2),4.15(2H,t,6.0Hz,-OCH2), 4.10-4.01(2H,m,-OCH2),2.30-2.26(2H,m,-CH2-),1.59-1.50(2H,m,-CH2-),1.28-1.21 (2H,m,-CH2-), 0.85 (3H, t, d=7.2Hz ,-CH3)；13C NMR(75MHz,CDCl3)δ:192.26,171.16, 159.45,158.95,155.41,137.83,136.23,130.16,129.14,128.61,128.45,128.28,128.25, 123.69,121.96,114.85,112.81,67.12,65.75,64.64,64.27,57.47,30.44,29.16,18.95, 13.67；HRMS:C30H33NO7[M+H]+Calculated value 520.2330, measured value 520.2333.
TM1-2a (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (2- formvlphenoxvs) propoxyl group) phenyl) acetic acid Methyl esters：White solid；m.p.:85-86℃；1H NMR(300MHz,DMSO-d6)δ:10.40(1H,s,CHO),8.22(1H,d,J =7.5Hz, NH), 7.62-7.70 (2H, m, Ar-H), 7.23-7.35 (m, 8H, Ar-H), 7.7 (1H, t, J=7.2Hz, Ar- ), H 6.93 (2H, d, J=7.8Hz, Ar-H), 5.20 (1H, d, J=7.5Hz, * CH), 5.05 (2H, s, PhCH2-),4.18- 4.29(4H,m,-OCH2),3.60(3H,s,OCH3),2.22-2.25(2H,m,-CH2-)；13C NMR(75MHz,DMSO-d6)δ: 189.3,171.6,160.9,158.4,155.9,136.9,136.5,129.2,128.4,127.9,127.8,127.7, 114.5,113.4,65.7,65.1,64.3,57.4,52.2,28.5；HRMS:C27H27NO7[M+Na]+Calculated value 500.1680, Measured value 500.1679.
TM1-2b (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (2- formvlphenoxvs) propoxyl group) phenyl) acetic acid Ethyl ester：White solid；m.p.:65-66℃；1H NMR(300MHz,CDCl3)δ:10.49(1H,s,CHO),7.85-7.79(1H, m,Ar-H),7.58-7.49(1H,m,Ar-H),7.40-7.14(7H,m,Ar-H),7.08-7.00(2H,m,Ar-H),6.98 (2H, d, J=9Hz, Ar-H), 5.80 (1H, d, J=6Hz, NH), 5.28 (1H, d, J=9.3Hz, * CH), 5.16-5.00 (2H, m,PhCH2-), 4.28 (2H, t, J=6.9Hz ,-OCH2),4.23-4.02(4H,m,-OCH2),2.38-2.30(2H,m,- CH2-), 0.85 (3H, t, J=7.5Hz ,-CH3)；13C NMR(151MHz,CDCl3)δ:189.64,171.06,161.27, 158.97,155.46,136.35,136.03,129.35,128.65,128.63,128.55,128.25,125.12,120.96, 114.96,112.63,67.16,65.18,64.36,61.94,57.56,29.29,14.11；HRMS:C28H29NO7[M+Na]+Meter Calculation value 514.1836, measured value 514.1840.
TM1-2c (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (2- formvlphenoxvs) propoxyl group) phenyl) acetic acid Propyl ester：White solid；m.p.:69-70℃；1H NMR(300MHz,CDCl3)δ:10.49(1H,s,CHO),7.95-7.76(1H, m,Ar-H),7.59-7.46(1H,m,Ar-H),7.42-7.13(7H,m,Ar-H),7.09-6.93(2H,m,Ar-H),6.98 (2H, d, J=7.8Hz, Ar-H), 5.82 (1H, d, J=6.6Hz, NH), 5.30 (1H, d, J=3.6Hz, * CH), 5.16-5.00 (2H,m,PhCH2-), 4.28 (2H, t, J=5.7Hz ,-OCH2), 4.17 (2H, t, J=5.7Hz ,-OCH2),4.08(2H,t,J =6.0Hz ,-OCH2),2.43-2.24(2H,m,-CH2-),1.64-1.46(2H,m,-CH2-), 0.82 (3H, t, J= 7.2Hz,-CH3)；13C NMR(151MHz,CDCl3)δ:189.63,171.15,161.27,158.96,155.47,136.36, 136.02,129.43,128.66,128.62,128.53,128.23,125.13,120.96,114.95,112.64,67.46, 67.16,65.20,64.38,57.57,29.29,21.92,10.23；HRMS:C29H31NO7[M+Na]+Calculated value 528.1993, Measured value 528.1998.
TM1-2d (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (2- formvlphenoxvs) propoxyl group) phenyl) acetic acid Butyl ester：White solid；m.p.:82-84℃；1H NMR(300MHz,CDCl3)δ:10.49(1H,s,CHO),7.87-7.79(1H, m,Ar-H),7.59-7.49(1H,m,Ar-H),7.40-7.12(7H,m,Ar-H),7.07-6.96(2H,m,Ar-H),6.88 (2H, d, J=8.7Hz, Ar-H), 5.84 (1H, d, J=7.9Hz, NH), 5.28 (1H, d, J=7.5Hz, * CH), 5.17-5.01 (2H,m,PhCH2-), 4.28 (2H, t, J=6.0Hz ,-OCH2), 4.18 (2H, t, J=6.0Hz ,-OCH2),4.14-4.01 (2H,m,-OCH2),2.40-2.25(2H,m,-CH2-),1.59-1.47(2H,m,-CH2-),0.92-0.78(5H,m,- CH2-,-CH3)；13C NMR(75MHz,CDCl3)δ:189.61,189.51,171.09,161.19,158.86,155.41, 136.28,136.03,135.94,129.28,128.52,128.46,128.17,124.91,120.86,114.83,112.52, 67.05,65.70,65.12,65.03,64.31,64.24,57.49,30.42,29.74,29.17,18.91,13.62, 13.56.
TM1-3a (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (4- formvlphenoxvs) propoxyl group) phenyl) acetic acid Methyl esters：White solid；m.p.:91-92℃；1H NMR(300MHz,CDCl3)δ:9.88 (1H, s, CHO), 7.83 (2H, d, J= 8.7Hz, Ar-H), 7.26-7.34 (7H, m, Ar-H), 7.01 (2H, d, J=8.4Hz, Ar-H), 6.89 (2H, d, J=8.4Hz, Ar-H), 5.79 (1H, d, J=6.6Hz, NH), 5.30 (1H, d, J=6.9Hz, * CH), 5.09 (2H, d, J=5.7Hz, PhCH2-),4.13-4.24(4H,m,H-6,-OCH2),3.71(3H,s,OCH3),2.27-2.31(2H,m,-CH2-)；13C NMR (75MHz,CDCl3)δ:190.5,171.1,163.4,158.5,155.0,135.7,131.6,129.5,128.5,128.1, 127.8,127.7,114.4,114.3,66.6,64.3,63.7,56.9,52.4,28.6；HRMS:C27H27NO7[M+Na]+Calculate Value 500.1680, measured value 500.1685.
TM1-3b (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (4- formvlphenoxvs) propoxyl group) phenyl) acetic acid Ethyl ester：White solid；m.p.:85-86℃；1H NMR(300MHz,CDCl3)δ:9.88 (1H, s, CHO), 7.83 (2H, d, J= 8.4Hz, Ar-H), 7.34-6.99 (7H, m, Ar-H), 7.01 (2H, d, J=8.4Hz, Ar-H), 6.88 (2H, d, J=8.4Hz, ), Ar-H 5.81 (1H, d, J=6.9Hz, NH), 5.28 (1H, d, J=7.5Hz, * CH)), 5.14-5.03 (2H, m, PhCH2-), 4.24 (2H, t, J=6.0Hz ,-OCH2-), 4.18 (2H, t, J=6.0Hz ,-OCH2-),4.26-4.09(2H,m,-OCH2-), 2.33-2.26(2H,m,-CH2-), 1.20 (3H, t, J=6.0Hz ,-CH3)；13C NMR(151MHz,CDCl3)δ:190.84, 171.07,164.00,158.99,155.45,136.33,132.10,130.18,129.32,128.63,128.53,128.25, 114.96,114.90,77.37,77.16,76.95,67.17,64.90,64.28,61.95,57.55,29.21,14.11； HRMS:C28H29NO7[M+Na]+Calculated value 514.1836, measured value 514.1840.
TM1-3c (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (4- formvlphenoxvs) propoxyl group) phenyl) acetic acid Propyl ester：Yellow oil；1H NMR(300MHz,CDCl3)δ:9.88 (1H, s, CHO), 7.83 (2H, d, J=8.4Hz, Ar-H), 7.36-7.26 (7H, m, Ar-H), 7.01 (2H, d, J=8.4Hz, Ar-H), 6.88 (2H, d, J=8.4Hz, Ar-H), 5.82 (1H, d, J=6.9Hz, NH), 5.29 (1H, d, J=7.5Hz, * CH), 5.14-5.03 (2H, m, PhCH2-),4.24(2H,t,J =6.0Hz ,-OCH2-), 4.15 (2H, t, J=6.0Hz ,-OCH2-),4.11-4.04(2H,m,-OCH2-),2.31-2.18 (2H,m,-CH2-),1.62-1.53(2H,m,-CH2-), 0.82 (3H, t, J=7.5Hz ,-CH3)；13C NMR(151MHz, CDCl3)δ:190.85,171.16,164.01,158.98,155.46,136.32,132.11,130.19,129.40, 128.63,128.50,128.25,114.94,114.90,77.37,77.16,76.95,67.46,67.17,64.91,64.30, 57.55,29.21,21.92,10.23；HRMS:C29H31NO7[M+Na]+Calculated value 528.1993, measured value 528.1996.
TM1-3d (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (4- formvlphenoxvs) propoxyl group) phenyl) acetic acid Butyl ester：White solid；m.p.:77-79℃；1H NMR(300MHz,CDCl3)δ:9.88 (1H, s, CHO), 7.83 (2H, d, J= 8.7Hz, Ar-H), 7.34-7.26 (7H, m, Ar-H), 7.01 (2H, d, J=8.7Hz, Ar-H), 6.88 (2H, d, J=8.7Hz, ), Ar-H 5.82 (1H, d, J=6.9Hz, NH), 5.29 (1H, d, J=7.5Hz, * CH), 55.14-5.03 (2H, m, PhCH2-), 4.24 (2H, t, J=6.0Hz ,-OCH2-),4.17-4.06(4H,m,-OCH2-),2.33-2.26(2H,m,-CH2-),1.59- 1.49(2H,m,-CH2-),1.28-1.21(2H,m,-CH2-), 0.85 (3H, t, J=7.2Hz ,-CH3)；13C NMR(151MHz, CDCl3)δ:190.82,171.14,163.98,158.96,155.44,136.32,132.09,130.16,129.37, 128.61,128.48,128.24,114.92,114.88,67.14,65.76,64.88,64.28,57.54,30.49,29.19, 18.97,13.64；HRMS:C30H33NO7[M+H]+Calculated value 520.2330, measured value 520.2332.
TM1-4a (R) -4- (3- (4- (1- ((benzyloxycarbonyl group) amino) -2- methoxyl group -2- oxoethyls) phenoxy group) third oxygen Base) methyl benzoate：White solid；m.p.:83-84℃；1H NMR(300MHz,CDCl3)δ:7.98 (2H, d, J=8.7Hz, ), Ar-H 7.26-7.34 (7H, m, Ar-H), 6.90 (4H, t, J=8.4Hz, Ar-H), 5.78 (1H, d, J=6.9Hz, NH), 5.30 (1H, d, J=6.9Hz, * CH), 5.09 (2H, d, J=5.4Hz, PhCH2-),4.15-4.22(4H,m,-OCH2-),3.88 (3H,s,-OCH3),3.71(3H,s,-OCH3),2.23-2.31(2H,m,-CH2-)；13C NMR(75MHz,CDCl3)δ: 171.1,166.4,162.1,158.5,154.9,135.7,131.2,128.4,128.1,128.0,127.8,127.7, 122.2,114.4,113.6,66.7,64.0,63.8,56.9,52.4,51.5,28.6；HRMS:C28H29NO8[M+Na]+Calculate Value 530.1785, measured value 530.1789.
TM1-4b (R) -4- (3- (4- (1- ((benzyloxycarbonyl group) amino) -2- ethyoxyl -2- oxoethyls) phenoxy group) third oxygen Base) methyl benzoate：White solid；m.p.:79-81℃；1H NMR(300MHz,CDCl3)δ:8.01 (2H, d, J=8.7Hz, Ar-H),7.99-7.28(7H,m,Ar-H),6.95-6.89(4H,m,Ar-H),5.82-5.80(1H,m,NH),5.31-5.29 (1H,m,*CH),5.16-5.05(2H,m,PhCH2-),4.24-4.11(6H,m,-OCH2-),3.90(3H,s,-OCH3), 2.31-2.27(2H,m,-CH2-), 1.20 (3H, t, J=6.9Hz ,-CH3)；13C NMR(151MHz,CDCl3)δ:171.09, 166.92,162.74,159.06,155.46,136.36,131.73,129.28,128.63,128.52,128.31,128.26, 122.88,114.99,114.23,67.17,64.71,64.43,61.93,57.58,51.92,29.28,14.11；HRMS: C29H31NO8[M+Na]+Calculated value 544.1942, measured value 544.1946.
TM1-4c (R) -4- (3- (4- (1- ((benzyloxycarbonyl group) amino) -2- oxo -2- Amongs) phenoxy group) third oxygen Base) methyl benzoate：White solid；m.p.:68-71℃；1H NMR(300MHz,CDCl3)δ:8.00 (2H, d, J=8.7Hz, Ar-H),7.97-7.26(7H,m,Ar-H),6.93-6.86(4H,m,Ar-H),5.82-5.80(1H,m,NH),5.30-5.28 (1H,m,*CH),5.14-5.03(2H,m,PhCH2-),4.22-4.11(6H,m,-OCH2-),3.88(3H,s,-OCH3), 2.29-2.26(2H,m,-CH2-),1.57-1.55(2H,m,-CH2-), 0.82 (3H, t, J=7.5Hz ,-CH3)；13C NMR (151MHz,CDCl3)δ:171.17,166.92,162.74,159.05,155.46,136.37,131.73,129.36, 128.63,128.49,128.27,122.88,114.98,114.23,67.45,67.17,64.72,64.44,57.58, 51.93,29.81,29.28,21.93,10.24；HRMS:C30H33NO8[M+Na]+Calculated value 558.2098, measured value 558.2102.
TM1-4d (R) -4- (3- (4- (1- ((benzyloxycarbonyl group) amino) -2- oxo -2- butoxyethyl groups) phenoxy group) third oxygen Base) methyl benzoate：White solid；m.p.:91-93℃；1H NMR(300MHz,CDCl3)δ:8.00 (2H, d, J=8.7Hz, Ar-H),7.97-7.26(7H,m,Ar-H),6.93-6.86(4H,m,Ar-H),5.82-5.80(1H,m,NH),5.30-5.27 (1H,m,*CH),5.14-5.03(2H,m,PhCH2-),4.22-4.07(6H,m,-OCH2-),3.88(3H,s,-OCH3), 2.31-2.24(2H,m,-CH2-),1.56-1.49(2H,m,-CH2-),1.28-1.21(2H,m,-CH2-),0.85(3H,t,J =7.2Hz ,-CH3)；13C NMR(151MHz,CDCl3)δ:171.15,166.91,162.73,159.04,155.46, 136.37,131.72,129.35,128.62,128.48,128.25,128.25,122.88,114.97,114.22,67.15, 65.75,64.71,64.45,57.58,51.91,30.52,29.27,18.99,13.64；HRMS:C31H35NO8[M+Na]+Calculate Value 572.2255, measured value 572.2260.
TM1-5a (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (4- (2- methoxyl group -2- oxoethyls) phenoxy group) Propoxyl group) phenyl) methyl acetate：White solid；m.p.:70-72℃；1H NMR(300MHz,CDCl3)δ:7.17-7.34(9H, M, Ar-H), 6.84-6.89 (4H, m, Ar-H), 5.78 (1H, d, J=6.9Hz, NH), 5.30 (1H, d, J=7.2Hz, * CH), 5.09 (2H, d, J=5.1Hz, PhCH2-),4.12-4.15(4H,m,-OCH2-),3.71(3H,s,-OCH3),3.68(3H,s,- OCH3),3.56(2H,s,-CH2-),2.20-2.28(2H,m,-CH2-)；13C NMR(75MHz,CDCl3)δ:172.0,171.1, 158.6,157.5,154.9,135.7,129.9,128.3,128.1,128.0,127.8,125.7,114.5,114.1,66.7, 64.0,63.8,56.9,52.4,51.6,39.9,29.3；HRMS:C29H31NO8[M+Na]+Calculated value 544.1942, measured value 544.1946.
TM1-5b (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (4- (2- ethyoxyl -2- oxoethyls) phenoxy group) Propoxyl group) phenyl) methyl acetate：White solid；m.p.:73-75℃；1H NMR(300MHz,CDCl3)δ:7.34-7.17(9H, m,Ar-H),6.94-6.83(4H,m,Ar-H),5.80-5.78(1H,m,NH),5.29-5.27(1H,m,*CH),5.14-5.04 (2H,m,PhCH2-),4.29-4.02(6H,m,-OCH2-),3.68(3H,s,-OCH3),3.56(2H,s,-CH2-),2.31- 2.17(2H,m,-CH2-), 1.20 (3H, t, J=6.6Hz ,-CH3)；13C NMR(151MHz,CDCl3)δ:172.40,171.12, 159.15,158.12,155.47,136.38,130.40,129.11,128.62,128.49,128.25,126.36,120.45, 115.01,114.78,67.15,64.65,64.53,61.91,57.59,52.05,40.41,29.39,14.11；HRMS: C30H33NO8[M+Na]+Calculated value 558.2098, measured value 558.2101.
TM1-5c (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (4- (2- oxo -2- Amongs) phenoxy group) Propoxyl group) phenyl) methyl acetate：White solid；m.p.:49-51℃；1H NMR(300MHz,CDCl3)δ:7.34-7.17(9H, m,Ar-H),6.93-6.81(4H,m,Ar-H),5.83-5.81(1H,m,NH),5.30-5.28(1H,m,*CH),5.14-5.04 (2H,m,PhCH2-),4.15-3.98(6H,m,-OCH2-),3.68(3H,s,-OCH3),3.56(2H,s,-CH2-),2.26- 2.22(2H,m,-CH2-),1.62-1.55(2H,m,-CH2-), 0.82 (3H, t, J=7.5Hz ,-CH3)；13C NMR(151MHz, CDCl3)δ:172.40,171.19,159.13,158.12,155.47,136.37,130.40,129.20,128.61, 128.46,128.24,126.36,120.44,114.99,114.78,67.42,67.15,64.65,64.53,57.59, 52.04,40.40,29.39,21.92,10.23；HRMS:C31H35NO8[M+Na]+Calculated value 572.2255, measured value 572.2260.
TM1-5d (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (4- (2- oxo -2- butoxyethyl groups) phenoxy group) Propoxyl group) phenyl) methyl acetate：White solid；m.p.:59-62℃；1H NMR(300MHz,CDCl3)δ:7.34-7.17(9H, m,Ar-H),6.96-6.73(4H,m,Ar-H),5.82-5.79(1H,m,NH),5.29-5.27(1H,m,*CH),5.14-5.04 (2H,m,*CH),4.15-3.98(6H,m,-OCH2-),3.68(3H,s,-OCH3),3.56(2H,s,-CH2-),2.26-2.22 (2H,m,-CH2-),1.56-1.52(2H,m,-CH2-),1.25-1.17(2H,m,-CH2-), 0.85 (3H, t, J=7.5Hz ,- CH3)；13C NMR(151MHz,CDCl3)δ:172.40,171.20,159.14,158.12,155.47,136.38,130.40, 129.20,128.62,128.46,128.25,128.23,126.36,115.00,114.78,67.15,65.74,64.67, 64.54,57.60,52.05,40.41,30.53,29.39,18.99,13.65；HRMS:C32H37NO8[M+Na]+Calculated value 586.2411, measured value 586.2416.
TM1-6a (R) -3- (4- (3- (4- (1- ((benzyloxycarbonyl group) amino) -2- methoxyl group -2- oxoethyls) phenoxy group) Propoxyl group) phenyl) methyl propionate：Yellow oil；1H NMR(300MHz,CDCl3)δ:7.26-7.34(7H,m,Ar-H), 7.11 (2H, d, J=8.4Hz, Ar-H), 6.81-6.89 (4H, m, Ar-H), 5.78 (1H, d, J=6.9Hz, NH), 5.30 (1H, D, J=6.9Hz, * CH), 5.09 (2H, d, J=4.8Hz, PhCH2-),4.09-4.15(4H,m,-OCH2-),3.71(3H,s,- OCH3),3.66(3H,s,-OCH3), 2.89 (2H, t, J=7.5Hz ,-CH2-), 2.59 (2H, t, J=7.5Hz ,-CH2-), 2.20-2.25(2H,m,-CH2-)；13C NMR(75MHz,CDCl3)δ:173.0,171.1,158.7,156.9,154.9, 135.7,132.3,128.8,128.3,128.1,128.0,127.8,127.7,114.5,114.1,66.7,64.0,63.8, 56.9,52.3,51.2,35.6,29.7,28.8；HRMS:C30H33NO8[M+H]+Calculated value 536.2279, measured value 536.2281.
TM1-6b (R) -3- (4- (3- (4- (1- ((benzyloxycarbonyl group) amino) -2- ethyoxyl -2- oxoethyls) phenoxy group) Propoxyl group) phenyl) methyl propionate：White solid；m.p.:53-54℃；1H NMR(300MHz,CDCl3)δ:7.37-7.26(7H, M, Ar-H), 7.10 (2H, d, J=8.4Hz, Ar-H), 6.89-6.81 (4H, m, Ar-H), 5.81-5.79 (1H, m, NH), 5.29-5.27(1H,m,*CH),5.14-5.04(2H,m,PhCH2-),4.19-4.10(6H,m,-OCH2-),3.66(3H,m,- OCH3), 2.89 (2H, t, J=6.6Hz ,-CH2-), 2.59 (2H, t, J=6.0Hz ,-CH2-),2.26-2.22(2H,m,- CH2-), 1.20 (3H, t, J=7.2Hz ,-CH3)；13C NMR(151MHz,CDCl3)δ:173.45,171.10,159.15, 157.47,155.45,136.37,132.88,129.33,129.09,128.63,128.60,128.47,128.23,114.99, 114.70,67.14,64.67,64.50,61.89,57.57,51.62,36.08,30.22,29.42,14.10；HRMS: C31H35NO8[M+H]+Calculated value 550.2435, measured value 550.2440.
TM1-6c (R) -3- (4- (3- (4- (1- ((benzyloxycarbonyl group) amino) -2- oxo -2- Amongs) phenoxy group) Propoxyl group) phenyl) methyl propionate：White solid；m.p.:50-51℃；1H NMR(300MHz,CDCl3)δ:7.37-7.27(7H, M, Ar-H), 7.10 (2H, d, J=8.4Hz, Ar-H), 6.89-6.81 (4H, m, Ar-H), 5.83-5.80 (1H, m, NH), 5.30-5.28(1H,m,*CH),5.14-5.04(2H,m,PhCH2-),4.15-4.04(6H,m,-OCH2-),3.66(3H,m,- OCH3), 2.89 (2H, t, J=6.6Hz ,-CH2-), 2.59 (2H, t, J=6.0Hz ,-CH2-),2.26-2.22(2H,m,- CH2-),1.62-1.55(2H,m,-CH2-), 0.82 (3H, t, J=7.5Hz ,-CH3)；13C NMR(151MHz,CDCl3)δ: 173.46,171.19,159.14,157.48,155.46,136.37,132.88,129.34,129.16,128.64,128.60, 128.44,128.23,114.98,114.70,67.41,67.14,64.69,64.52,57.59,51.62,36.08,30.22, 29.42,21.92,10.22；HRMS:C32H37NO8[M+Na]+Calculated value 586.2411, measured value 586.2415.
TM1-6d (R) -3- (4- (3- (4- (1- ((benzyloxycarbonyl group) amino) -2- oxo -2- butoxyethyl groups) phenoxy group) Propoxyl group) phenyl) methyl propionate：White solid；m.p.:44-46℃；1H NMR(300MHz,CDCl3)δ:7.37-7.26(7H, M, Ar-H), 7.10 (2H, d, J=8.4Hz, Ar-H), 6.89-6.81 (4H, m, Ar-H), 5.82-5.79 (1H, m, NH), 5.29-5.27(1H,m,*CH),5.14-5.04(2H,m,PhCH2-),4.15-4.06(6H,m,-OCH2-),3.66(3H,m,- OCH3), 2.89 (2H, t, J=6.6Hz ,-CH2-), 2.59 (2H, t, J=7.2Hz ,-CH2-),2.26-2.20(2H,m,- CH2-),1.57-1.50(2H,m,-CH2-),1.29-1.21(2H,m,-CH2-), 0.85 (3H, t, J=7.5Hz ,-CH3)；13C NMR(151MHz,CDCl3)δ:173.46,171.19,159.15,157.49,155.46,136.38,132.90,129.35, 129.18,128.65,128.61,128.45,128.25,114.99,114.71,67.15,65.74,64.71,64.52, 57.59,51.63,36.09,30.52,30.23,29.43,18.99,13.64；HRMS:C33H39NO8[M+Na]+Calculated value 600.2568, measured value 600.2572.
TM1-7a (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (4- propionyl phenoxy group)-propoxyl group) phenyl) acetic acid Methyl esters：White solid；m.p.:86-87℃；1H NMR(300MHz,CDCl3)δ:7.93 (2H, d, J=8.7Hz, Ar-H), 7.26-7.34 (6H, m, Ar-H), 6.87-6.95 (5H, m, Ar-H), 5.79 (1H, d, J=6.9Hz, NH), 5.29 (1H, d, J =7.2Hz, * CH), 5.09 (2H, q, J=12.3Hz, 18.6Hz, PhCH2-),4.13-4.24(6H,m,-OCH2-),2.55 (3H,s,-OCH3),2.24-2.32(2H,m,-CH2-), 1.20 (3H, t, J=6.9Hz ,-CH3)；13C NMR(75MHz, CDCl3)δ:196.4,170.6,162.3,158.4,154.9,135.7,130.2,129.9,128.6,128.1,128.0, 127.8,127.7,114.4,113.7,66.6,64.1,63.7,61.5,57.0,29.3,26.0,13.6；HRMS:C29H31NO7 [M+Na]+Calculated value 528.1993, measured value 528.2000.
TM1-7b (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (4- propionyl phenoxy group)-propoxyl group) phenyl) acetic acid Ethyl ester：White solid；m.p.:93-95℃；1H NMR(300MHz,CDCl3)δ:1.18-1.23(m,6H,2-CH3),2.24- 2.32(m,2H,-CH2-), 2.95 (q, 2H, J=7.2Hz, 14.4Hz, CH2),4.13-4.23(m,6H,2-OCH2),5.08(q, 2H, J=12.3Hz, 18.6Hz, PhCH2), 5.28 (d, 1H, J=7.2Hz, * CH), 5.79 (d, 1H, J=6.9Hz, CONH), 6.87-6.94 (m, 4H, Ar-H), 7.26-7.34 (m, 6H, Ar-H), 7.94 (d, 2H, J=8.7Hz, Ar-H)；13C NMR (75MHz,DMSO-d6)δ:198.8,171.6,162.2,158.4,155.9,136.9,130.1,129.1,128.4,127.9, 127.8,114.5,114.3,65.7,64.6,64.1,57.4,52.2,30.8,28.5,8.3；HRMS:C30H33NO7[M+Na]+ Calculated value 542.2149, measured value 542.2152.
TM1-7c (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (4- propionyl phenoxy group)-propoxyl group) phenyl) acetic acid Propyl ester：White solid；m.p.:86-87℃；1H NMR(300MHz,CDCl3)δ:7.94 (2H, d, J=8.7Hz, Ar-H), 7.34-7.26 (7H, m, Ar-H), 6.93 (2H, d, J=8.7Hz, Ar-H), 6.88 (2H, d, J=8.7Hz, Ar-H), 5.81 (1H, d, J=7.2Hz, NH), 5.29 (1H, d, J=6.9Hz, * CH), 5.14-5.03 (2H, m, PhCH2-),4.21(2H,t,J =6.0Hz ,-OCH2-), 4.15 (2H, t, J=6.0Hz ,-OCH2-),4.11-4.04(2H,m,-OCH2-),2.95(2H,q,J =7.2Hz ,-CH2-),2.32-2.24(2H,m,-CH2-),1.62-1.55(2H,m,-CH2-), 1.21 (3H, t, J= 7.2Hz,-CH3), 0.82 (3H, t, J=7.5Hz ,-CH3)；13C NMR(151MHz,CDCl3)δ:199.59,171.18, 162.72,159.04,155.46,136.35,130.37,130.27,129.35,128.65,128.50,128.28,114.97, 114.29,67.48,67.19,64.73,64.40,57.57,31.54,29.28,21.93,10.25,8.58；HRMS: C31H35NO7[M+Na]+Calculated value 556.2306, measured value 556.2309.
TM1-7d (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (4- propionyl phenoxy group)-propoxyl group) phenyl) acetic acid Butyl ester：White solid；m.p.:75-76℃；1H NMR(300MHz,CDCl3)δ:7.94 (2H, d, J=7.1Hz, Ar-H), 7.34-7.26 (7H, m, Ar-H), 6.95-6.87 (4H, m, Ar-H), 5.81 (1H, d, J=6.6Hz, NH), 5.29 (1H, d, J =7.2Hz, * CH), 5.14-5.03 (2H, m, PhCH2-), 4.21 (2H, t, J=5.7Hz ,-OCH2-), 4.15 (2H, t, J= 6.0Hz,-OCH2-),4.17-4.07(2H,m,-OCH2-), 2.95 (2H, q, J=7.2Hz ,-CH2-),2.30-2.26(2H, m,-CH2-),1.59-1.50(2H,m,-CH2-),1.26-1.19(2H,m,-CH2-), 0.85 (3H, t, J=7.2Hz ,-CH3) ；13C NMR(151MHz,CDCl3)δ:199.57,171.16,162.70,159.03,155.45,136.34,130.35, 130.26,129.34,128.63,128.49,128.26,114.96,114.28,67.17,65.78,64.72,64.41, 57.57,31.52,30.52,29.26,18.99,13.65,8.57；HRMS:C32H37NO7[M+Na]+Calculated value 570.2462, it is real Measured value 570.2466.
TM1-8a (R) -2- (4- (3- (4- acetyl phenoxy group) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) amino) acetic acid first Ester：White solid；m.p.:99-100℃；1H NMR(300MHz,DMSO-d6)δ:8.22 (1H, d, J=7.8Hz, NH), 7.92 (2H, d, J=8.7Hz, Ar-H), 7.29-7.35 (7H, m, Ar-H), 7.05 (2H, d, J=8.7Hz, Ar-H), 6.93 (2H, d, J=8.7Hz, Ar-H), 5.19 (1H, d, J=7.5Hz, * CH), 5.04 (2H, s, PhCH2-),4.10-4.23(4H,m,- OCH2-),3.59(3H,s,-OCH3),2.50(3H,s,-CH3),2.16-2.20(2H,m,-CH2-)；13C NMR(75MHz, DMSO-d6)δ:196.3,171.6,162.4,158.4,155.9,136.9,130.5,129.9,129.2,128.4,128.3, 127.9,127.8,114.5,114.3,65.7,64.6,64.1,57.4,52.2,28.5,26.4；HRMS:C28H29NO7[M+Na ]+Calculated value 514.1836, measured value 514.1842.
TM1-8b (R) -2- (4- (3- (4- acetyl phenoxy group) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) amino) acetic acid second Ester：White solid；m.p.:106-107℃；1H NMR(300MHz,CDCl3)δ:7.93 (2H, d, J=8.7Hz, Ar-H), 7.26-7.34 (6H, m, Ar-H), 6.87-6.95 (5H, m, Ar-H), 5.79 (1H, d, J=6.9Hz, NH), 5.29 (1H, d, J =7.2Hz, * CH), 5.09 (2H, q, J=12.3Hz, 18.6Hz, PhCH2-),4.13-4.24(6H,m,-OCH2-),2.55 (3H,s,-CH3),2.24-2.32(2H,m,-CH2-), 1.20 (3H, t, J=6.9Hz ,-CH3)；13C NMR(75MHz,CDCl3) δ:196.4,170.6,162.3,158.4,154.9,135.7,130.2,129.9,128.6,128.1,128.0,127.8, 127.7,114.4,113.7,66.6,64.1,63.7,61.5,57.0,29.3,26.0,13.6；HRMS:C29H31NO7[M+Na]+ Calculated value 528.1993, measured value 528.1996.
TM1-8c (R) -2- (4- (3- (4- acetyl phenoxy group) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) amino) acetic acid third Ester：White solid；m.p.:79-81℃；1H NMR(300MHz,CDCl3)δ:7.93 (2H, d, J=7.8Hz, Ar-H), 7.34- 7.26(7H,m,Ar-H),6.95-6.87(4H,m,Ar-H),5.82(1H,m,NH),5.29(1H,m,*CH),5.14-5.03 (2H,m,PhCH2-), 4.22 (2H, t, J=6.0Hz ,-OCH2-), 4.15 (2H, t, J=6.0Hz ,-OCH2-),4.24-4.13 (2H,m,-OCH2-),2.56(3H,s,-CH3),2.32-2.24(2H,m,-CH2-),1.57-1.49(2H,m,-CH2-),0.85 (3H, t, J=7.2Hz ,-CH3)；13C NMR(151MHz,CDCl3)δ:196.85,171.16,162.88,159.00, 155.46,136.31,130.70,130.55,129.33,128.61,128.47,128.23,114.94,114.28,77.37, 77.16,76.95,67.44,67.15,64.74,64.36,57.55,29.23,26.37,21.90,10.22；HRMS: C30H33NO7[M+Na]+Calculated value 542.2149, measured value 542.2154.
TM1-8d (R) -2- (4- (3- (4- acetyl phenoxy group) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) amino) acetic acid fourth Ester：White solid；m.p.:66-69℃；1H NMR(300MHz,CDCl3)δ:7.93 (2H, d, J=9.0Hz, Ar-H), 7.34- 7.26(7H,m,Ar-H),6.95-6.87(4H,m,Ar-H),5.82(1H,m,NH),5.30(1H,m,*CH),5.15-5.05 (2H,m,PhCH2-), 4.23 (2H, t, J=5.7Hz ,-OCH2-), 4.17 (2H, t, J=6.0Hz ,-OCH2-),4.13-4.04 (2H,m,-OCH2-),2.57(3H,s,-CH3),2.32-2.28(2H,m,-CH2-),1.61-1.57(2H,m,-CH2-), 1.45-1.41(2H,m,-CH2-), 0.84 (3H, t, J=7.2Hz ,-CH3)；13C NMR(151MHz,CDCl3)δ:196.84, 171.17,162.90,159.03,155.46,136.34,130.73,130.59,129.36,128.63,128.49,128.26, 114.97,114.30,67.18,65.78,64.76,64.40,57.57,30.52,29.26,26.40,18.99,13.66； HRMS:C31H35NO7[M+Na]+Calculated value 556.2306, measured value 556.2311.
TM1-9a (R) -2- (4- (3- (2- acetylbenzenes epoxide) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) amino) acetic acid Methyl esters：Yellow oil；1H NMR(300MHz,CDCl3)δ:7.73 (2H, d, J=6.3Hz, Ar-H) .7.26-7.47 (7H, m, ), Ar-H 6.96-7.02 (2H, m, Ar-H), 6.88 (2H, d, J=8.4Hz, Ar-H), 5.79 (1H, d, J=6.9Hz, NH), 5.31 (1H, d, J=6.9Hz, * CH), 5.09 (2H, q, J=12.3Hz, 17.7Hz, PhCH2-),4.15-4.26(4H,m,- OCH2-),3.71(3H,s,-OCH3),3.62(3H,s,-CH3),2.29-2.37(2H,m,-CH3)；13C NMR(75MHz, CDCl3)δ:199.3,171.1,158.5,157.6,154.9,135.7,133.3,130.0,128.5,128.1,127.9, 127.8,127.7,120.3,114.4,111.9,66.7,64.6,63.9,56.9,52.4,31.6,28.8；HRMS:C28H29NO7 [M+Na]+Calculated value 514.1836, measured value 514.1841.
TM1-9b (R) -2- (4- (3- (2- acetylbenzenes epoxide) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) amino) acetic acid Ethyl ester：Yellow oil；1H NMR(300MHz,CDCl3)δ:7.73 (1H, d, J=4.2Hz, Ar-H), 7.50-7.49 (1H, m, Ar-H),7.38-7.20(7H,m,Ar-H),7.05-6.92(2H,m,Ar-H),6.92-6.79(2H,m,Ar-H),5.81(1H, D, J=6.3Hz, NH), 5.28 (1H, d, J=6.9Hz, * CH), 5.15-5.01 (2H, m, PhCH2-),4.30-4.07(6H, m,-OCH2-),2.62(3H,s,-CH3),2.40-2.24(2H,m,-CH2-),1.22-1.08(3H,m,-CH3)；13C NMR (151MHz,CDCl3)δ:199.69,171.05,158.96,158.16,155.45,136.34,133.68,130.49, 129.35,128.59,128.53,128.23,128.21,120.83,114.93,76.95,67.13,65.28,64.58, 61.91,57.55,31.96,29.37,14.09；HRMS:C29H31NO7[M+Na]+Calculated value 528.1993, measured value 528.1996.
TM1-9c (R) -2- (4- (3- (2- acetylbenzenes epoxide) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) amino) acetic acid Propyl ester：Yellow solid；m.p.:71-72℃；1H NMR(300MHz,CDCl3)δ:7.73 (1H, d, J=4.2Hz, Ar-H), 7.47-7.42(1H,m,Ar-H),7.38-7.21(7H,m,Ar-H),7.02-6.96(2H,m,Ar-H),6.89-6.86(2H, M, Ar-H), 5.81 (1H, d, J=6.9Hz, NH), 5.28 (1H, d, J=7.2Hz, * CH), 5.14-5.04 (2H, m, PhCH2-), 4.27 (2H, t, J=6.0Hz ,-OCH2-), 4.17 (2H, t, J=5.7Hz ,-OCH2-),4.12-4.04(2H,m,- OCH2-),2.62(3H,s,-CH3),2.37-2.30(2H,m,-CH2-),1.60-1.55(2H,m,-CH2-),0.84(3H,t,J =7.8Hz ,-CH3)；13C NMR(151MHz,CDCl3)δ:199.69,171.13,158.95,158.17,155.45, 136.35,133.68,130.50,129.44,128.60,128.51,128.25,128.22,126.67,120.84,114.92, 112.52,67.43,67.14,65.29,64.60,57.57,31.97,29.38,21.91,10.21；HRMS:C30H33NO7[M+ Na]+Calculated value 542.2149, measured value 542.2152.
TM1-9d (R) -2- (4- (3- (2- acetylbenzenes epoxide) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) amino) acetic acid Butyl ester：White solid；m.p.:82-84℃；1H NMR(300MHz,CDCl3)δ:7.73 (1H, d, J=4.2Hz, Ar-H), 7.48-7.42(1H,m,Ar-H),7.34-7.26(7H,m,Ar-H),7.02-6.96(2H,m,Ar-H),6.89-6.86(2H, M, Ar-H), 5.82 (1H, d, J=7.2Hz, NH), 5.29 (1H, d, J=7.2Hz, * CH), 5.14-5.04 (2H, m, PhCH2-), 4.27 (2H, t, J=6.0Hz ,-OCH2-),4.25-4.07(4H,m,-OCH2-),2.62(3H,s,-CH3), 2.36-2.32(2H,m,-CH2-),1.57-1.52(2H,m,-CH2-),1.29-1.21(2H,m,-CH2-),0.85(3H,t,J =7.5Hz ,-CH3)；13C NMR(151MHz,CDCl3)δ:199.67,171.11,158.94,158.16,155.44, 136.35,133.67,130.49,129.42,128.59,128.50,128.23,128.21,120.83,114.91,112.51, 67.13,65.74,65.29,64.60,57.55,31.96,30.50,29.37,18.96,13.62；HRMS:C31H35NO7[M+H ]+Calculated value 534.2486, measured value 534.2490.
TM1-10a (R) -2- (4- (3- (3- acetylbenzenes epoxide) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) amino) second Sour methyl esters：White solid；m.p.:94-95℃；1H NMR(300MHz,CDCl3)δ:7.26-7.55(10H,m,Ar-H),7.11 (1H, d, J=8.1Hz, Ar-H), 6.89 (2H, d, J=8.4Hz, Ar-H), 5.77 (1H, d, J=6.0Hz, NH), 5.30 (1H, D, J=6.0Hz, * CH), 5.09 (2H, q, J=12.3Hz, 17.1Hz, PhCH2-),4.14-4.20(4H,m,-OCH2-),3.72 (3H,s,-OCH3),2.59(3H,s,-CH3),2.25-2.29(2H,m,-CH2-)；13C NMR(75MHz,CDCl3)δ:198.0, 171.7,159.1,159.1,155.4,138.5,136.2,129.7,128.9,128.6,128.5,128.3,128.2, 121.3,120.1,115.0,113.1,67.2,64.6,64.3,57.4,52.9,29.8,26.9；HRMS:C28H29NO7[M+Na ]+Calculated value 514.1836, measured value 514.1837.
TM1-10b (R) -2- (4- (3- (3- acetylbenzenes epoxide) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) amino) second Acetoacetic ester：White solid；m.p.:81-83℃；1H NMR(300MHz,CDCl3)δ:7.57-7.45(2H,m,Ar-H),7.41- 7.24(8H,m,Ar-H),7.14-7.09(1H,m,Ar-H),6.92-6.85(2H,m,Ar-H),5.87-5.76(1H,m,NH), 5.33-5.24(1H,m,*CH),5.15-5.02(2H,m,PhCH2-),4.27-4.07(6H,m,-OCH2-),2.59(3H,s,- CH3),2.32-2.21(2H,m,-CH2-), 1.20 (3H, t, J=2.9Hz ,-CH3)；13C NMR(151MHz,CDCl3)δ: 197.94,171.09,159.21,159.08,155.46,138.69,136.36,129.69,129.17,128.60,128.49, 128.24,128.22,121.28,120.07,114.99,113.32,77.37,77.16,76.95,67.13,64.73, 64.47,61.90,57.57,29.31,26.75,14.09；HRMS:C29H31NO7[M+Na]+Calculated value 528.1993, measured value 528.1996.
TM1-10c (R) -2- (4- (3- (3- acetylbenzenes epoxide) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) amino) second Propyl propionate：White solid；m.p.:87-89℃；1H NMR(300MHz,CDCl3)δ:7.57-7.46(2H,m,Ar-H),7.42- 7.21(8H,m,Ar-H),7.15-7.07(1H,m,Ar-H),6.93-6.82(2H,m,Ar-H),5.87-5.78(1H,m,NH), 5.32-5.25(1H m,*CH),5.16-5.02(2H,m,PhCH2-),4.25-4.00(6H,m,-OCH2-),2.59(3H,s,- CH3),2.33-2.21(2H,m,-CH2-),1.63-1.50(2H,m,-CH2-), 0.82 (3H, t, J=7.5Hz ,-CH3)；13C NMR(151MHz,CDCl3)δ:197.91,171.14,162.63,159.18,159.03,155.44,138.66,136.34, 129.66,129.22,128.56,128.44,128.20,121.26,120.04,114.94,113.30,77.37,77.16, 76.95,67.38,67.09,64.71,64.46,57.56,29.28,26.71,21.88,10.19；HRMS:C30H33NO7[M+H ]+Calculated value 520.2330, measured value 520.2332.
TM1-10d (R) -2- (4- (3- (3- acetylbenzenes epoxide) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) amino) second Acid butyl ester：White solid；m.p.:69-70℃；1H NMR(300MHz,CDCl3)δ:7.59-7.42(2H,m,Ar-H),7.41- 7.17(8H,m,Ar-H),7.14-7.06(1H,m,Ar-H),6.94-6.79(2H,m,Ar-H),5.89-5.72(1H,m,NH), 5.33-5.21(1H,m,*CH),5.16-5.00(2H,m,PhCH2-),4.25-4.00(6H,m,-OCH2-),2.59(3H,s,- CH3),2.34-2.18(2H,m,-CH2-),1.57-1.44(2H,m,-CH2-),1.30-1.15(2H,m,-CH2-),0.87 (3H, t, J=7.2Hz ,-CH3)；13C NMR(151MHz,CDCl3)δ:197.96,171.18,159.24,159.09, 155.46,138.72,136.37,129.71,129.28,128.63,128.48,128.27,128.26,121.31,120.10, 115.00,113.33,77.37,77.16,76.95,67.16,65.76,64.75,64.52,57.59,30.53,29.34, 26.78,19.00,13.65；HRMS:C31H35NO7[M+Na]+Calculated value 556.2306, measured value 556.2311.
TM1-11a (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (5- formoxyl -2- methoxyphenoxies) third oxygen Base) phenyl) methyl acetate：White solid；m.p.:113-115℃；1H NMR(300MHz,CDCl3)δ:9.83(1H,s,CHO), 7.26-7.47 (9H, m, Ar-H), 6.97 (1H, d, J=8.1Hz, Ar-H), 6.89 (2H, d, J=8.7Hz, Ar-H), 5.77 (1H, d, J=6.9Hz, NH), 5.30 (1H, d, J=7.2Hz, * CH), 5.09 (2H, d, J=4.8Hz, PhCH2-),4.27 (2H, t, J=6.0Hz ,-OCH2-), 4.17 (2H, t, J=6.0Hz ,-OCH2-),3.93(3H,s,-OCH3),3.71(3H,s,- OCH3),2.29-2.37(2H,m-CH2-)；13C NMR(75MHz,CDCl3)δ:190.5,171.1,158.6,154.9,154.4, 148.4,135.7,129.6,128.3,128.1,128.0,127.8,127.7,126.4,114.5,110.2,110.0,66.6, 65.0,63.8,56.9,55.7,52.4,28.5；HRMS:C28H29NO8[M+Na]+Calculated value 530.1785, measured value 530.1789.
TM1-11b (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (5- formoxyl -2- methoxyphenoxies) third oxygen Base) phenyl) ethyl acetate：White solid；m.p.:124-126℃；1H NMR(300MHz,CDCl3)δ:9.84(1H,s,CHO), 7.47-7.44 (2H, m, Ar-H), 7.34-7.12 (7H, m, Ar-H), 6.97 (1H, d, J=7.2Hz, Ar-H), 6.89 (2H, d, J=8.4Hz, Ar-H), 5.80-5.78 (1H, m, NH), 5.29-5.27 (1H, m, * CH), 5.14-5.04 (2H, m, PhCH2-), 4.29-4.05(6H,m,-OCH2-),3.94(3H,s,-OCH3),2.37-2.30(2H,m,-CH2-), 1.20 (3H, t, J= 7.2Hz,-CH3)；13C NMR(75MHz,CDCl3)δ:191.02,171.09,158.99,155.40,154.87,148.92, 136.25,130.09,128.99,128.59,128.44,128.26,128.23,126.94,114.90,110.71,110.56, 67.10,65.51,64.33,61.92,57.49,56.20,29.07,14.09；HRMS:C29H31NO8[M+H]+Calculated value 522.2122, measured value 522.2127.
TM1-11c (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (5- formoxyl -2- methoxyphenoxies) third oxygen Base) phenyl) propyl acetate：White solid；m.p.:88-90℃；1H NMR(300MHz,CDCl3)δ:9.84(1H,s,CHO), 7.47-7.44 (2H, m, Ar-H), 7.34-7.12 (7H, m, Ar-H), 6.97 (1H, d, J=8.1Hz, Ar-H), 6.89 (2H, d, J=8.7Hz, Ar-H), 5.82-5.80 (1H, m, NH), 5.30-5.28 (1H, m, * CH), 5.14-5.04 (2H, m, PhCH2-), 4.27 (2H, t, J=6.0Hz ,-OCH2-), 4.17 (2H, t, J=5.7Hz ,-OCH2-),4.08-4.04(2H,m,-OCH2-), 3.94(3H,s,-OCH3),2.37-2.29(2H,m,-CH2-),1.64-1.53(2H,m,-CH2-), 0.82 (3H, t, J= 7.2Hz,-CH3)；13C NMR(75MHz,CDCl3)δ:191.03,171.18,158.98,155.41,154.88,148.93, 136.26,130.10,129.09,128.61,128.42,128.27,128.25,126.96,114.89,110.72,110.58, 67.42,67.11,65.54,64.35,57.50,56.21,29.08,21.87,10.25；HRMS:C30H33NO8[M+Na]+Calculate Value 558.2098, measured value 558.2102.
TM1-11d (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (5- formoxyl -2- methoxyphenoxies) third oxygen Base) phenyl) butyl acetate：White solid；m.p.:95-97℃；1H NMR(300MHz,CDCl3)δ:9.84(1H,s,CHO), 7.47-7.44 (2H, m, Ar-H), 7.34-7.12 (7H, m, Ar-H), 6.97 (1H, d, J=7.2Hz, Ar-H), 6.89 (2H, d, J=8.4Hz, Ar-H), 5.82-5.80 (1H, m, NH), 5.30-5.27 (1H, m, * CH), 5.14-5.04 (2H, m, PhCH2-), 4.27 (2H, t, J=6.0Hz ,-OCH2-), 4.17 (2H, t, J=5.7Hz ,-OCH2-),4.13-4.08(2H,m,-OCH2-), 3.93(3H,s,-OCH3),2.35-2.31(2H,m,-CH2-),1.57-1.50(2H,m,-CH2-),1.29-1.21(2H,m,H- 26-CH2-), 0.85 (3H, t, J=7.4Hz, H-27-CH3)；13C NMR(75MHz,CDCl3)δ:191.00,190.94, 171.13,158.96,155.38,154.87,148.91,136.25,130.08,130.05,129.05,128.55,128.38, 128.20,126.87,114.86,110.72,67.05,65.68,65.52,64.35,57.48,56.15,30.41,29.05, 18.91,13.62；HRMS:C31H35NO8[M+H]+Calculated value 550.2435, measured value 550.2440.
TM1-12a (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (4- formoxyl -2- methoxyphenoxies) third oxygen Base) phenyl) methyl acetate：White solid；m.p.:98-99℃；1H NMR(300MHz,CDCl3)δ:9.85(1H,s,CHO), 7.26-7.44 (9H, m, Ar-H), 7.00 (1H, d, J=7.8Hz, Ar-H), 6.89 (2H, d, J=8.4Hz, Ar-H), 5.77 (1H, d, J=6.9Hz, NH), 5.30 (1H, d, J=7.2Hz, * CH), 5.09 (2H, d, J=5.7Hz, PhCH2-),4.29 (2H, t, J=6.0Hz ,-OCH2-), 4.17 (2H, t, J=6.0Hz ,-OCH2-),3.91(3H,s,-OCH3),3.71(3H,s,- OCH3),2.31-2.39(2H,m,-CH2-)；13C NMR(75MHz,CDCl3)δ:190.5,171.1,158.5,154.9, 153.4,149.4,135.7,129.9,128.4,128.1,128.0,127.8,127.7,126.4,114.4,111.1, 108.7,66.6,65.1,64.9,63.7,56.9,55.5,52.4,28.5.HRMS:C28H29NO8[M+Na]+Calculated value 530.1785, measured value 530.1785.
TM1-12b (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (4- formoxyl -2- methoxyphenoxies) third oxygen Base) phenyl) ethyl acetate：Yellow oil；1H NMR(300MHz,CDCl3)δ:9.85(1H,s,CHO),7.45-7.26(9H, M, Ar-H), 7.01 (1H, d, J=8.1Hz, Ar-H), 6.89 (2H, d, J=8.4Hz, Ar-H), 5.82-5.80 (1H, m, NH), 5.29-5.27(1H,m,*CH),5.14-5.03(2H,m,PhCH2-), 4.30 (2H, t, J=6.0Hz ,-CH2-),4.17(2H, T, J=5.7Hz ,-CH2-),4.21-4.09(2H,m,-OCH2-),3.91(3H,s,-OCH3),2.37-2.33(2H,m,- CH2-), 1.20 (3H, t, J=7.2Hz, H-25-CH3)；13C NMR(75MHz,CDCl3)δ:191.07,171.06,158.91, 155.39,153.92,149.87,136.22,130.16,129.13,128.60,128.47,128.28,128.24,126.90, 114.87,111.56,109.23,67.12,65.61,64.21,61.95,57.46,56.04,29.03,14.09；HRMS: C29H31NO8[M+Na]+Calculated value 544.1942, measured value 544.1946.
TM1-12c (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (4- formoxyl -2- methoxyphenoxies) third oxygen Base) phenyl) propyl acetate：Yellow oil；1H NMR(300MHz,CDCl3)δ:9.85(1H,s,CHO),7.45-7.26(9H, M, Ar-H), 7.01 (1H, d, J=8.1Hz, Ar-H), 6.89 (2H, d, J=8.7Hz, Ar-H), 5.83-5.81 (1H, m, NH), 5.31-5.28(1H,m,*CH),5.14-5.03(2H,m,PhCH2-), 4.30 (2H, t, J=6.0Hz ,-OCH2-),4.17(2H, T, J=5.7Hz ,-OCH2-),4.11-4.09(2H,m,-OCH2-),3.91(3H,s,-OCH3),2.37-2.33(2H,m,- CH2-),1.60-1.55(2H,m,-CH2-), 0.82 (3H, t, J=7.5Hz ,-CH3)；13C NMR(75MHz,CDCl3)δ: 191.07,171.06,158.91,155.39,153.92,149.87,136.22,130.16,129.13,128.60,128.47, 128.28,128.24,126.90,114.87,111.56,109.23,67.12,65.61,64.21,61.95,57.46, 56.04,29.03,14.09；HRMS:C30H33NO8[M+H]+Calculated value 536.2279, measured value 536.2289.
TM1-12d (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (4- formoxyl -2- methoxyphenoxies) third oxygen Base) phenyl) butyl acetate：Yellow solid；m.p.:85-86℃；1H NMR(300MHz,CDCl3)δ:9.85(1H,s,CHO), 7.45-7.26 (9H, m, Ar-H), 7.01 (1H, d, J=8.1Hz, Ar-H), 6.89 (2H, d, J=8.4Hz, Ar-H), 5.83- 5.81(1H,m,NH),5.30-5.27(1H,m,*CH),5.14-5.03(2H,m,PhCH2-), 4.30 (2H, t, J=6.0Hz ,- OCH2-), 4.17 (2H, t, J=5.7Hz ,-OCH2-),4.13-4.07(2H,m,-OCH2-),3.91(3H,s,-OCH3), 2.37-2.33(2H,m,-CH2-),1.60-1.55(2H,m,-CH2-),1.57-1.50(2H,m,-CH2-),0.85(3H,t,J =7.5Hz ,-CH3)；13C NMR(75MHz,CDCl3)δ:191.05,171.12,158.87,155.37,153.89,149.85, 136.20,130.14,129.19,128.58,128.42,128.26,128.22,126.89,114.83,111.54,109.21, 67.08,65.73,65.59,64.21,57.45,56.02,30.41,29.01,18.92,13.65；HRMS:C31H35NO8[M+H ]+Calculated value 550.2435, measured value 550.2438.
TM1-13a (R)-2- (4- (3- (4- acetylaminos phenoxy group) propoxyl group) phenyl)-2-((benzyloxycarbonyl group) amino) Methyl acetate：Yellow oil；1H NMR(300MHz,CDCl3)δ:7.25-7.38(10H,m,NH,Ar-H),6.86(4H,t,J =8.7Hz, Ar-H 1), 5.80 (1H, d, J=6.3Hz, NH), 5.29 (1H, d, J=6.6Hz, * CH), 5.09 (2H, q, J= 8.1Hz,PhCH2-),4.12-4.13(4H,m,-OCH2-),3.71(3H,s,-OCH3),2.15-2.26(5H,m,-CH3and- CH2-)；13C NMR(75MHz,CDCl3)δ:171.1,168.3,158.6,155.1,155.0,135.7,130.9,128.7, 128.0,127.8,127.7,121.5,114.5,114.3,66.7,64.0,63.9,57.0,52.4,28.2,23.7；HRMS: C28H30N2O7[M+Na]+Calculated value 529.1945, measured value 529.1948.
TM1-13b (R) -2- (4- (3- (4- acetylaminos phenoxy group) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) amino) Ethyl acetate：White solid；m.p.:134-136℃；1H NMR(300MHz,CDCl3)δ:7.49-7.10(9H,m,Ar-H), 6.97-6.70(4H,m,Ar-H),5.84(1H,s,NH),5.29(1H,s,*CH),5.19-5.00(2H,m,PhCH2-), 4.40-3.99(6H,m,-OCH2-),2.37-2.09(5H,m,-CH3and-CH2-),1.27-1.14(3H,m,-CH3)；13C NMR(151MHz,CDCl3)δ:171.09,168.49,159.13,155.71,155.52,136.30,131.44,128.99, 128.59,128.45,128.26,128.17,121.98,115.00,114.91,77.37,77.16,76.95,67.15, 64.77,64.61,61.91,57.60,29.38,24.27,14.07；HRMS:C29H32N2O7[M+H]+Calculated value 521.2282, Measured value 521.2286.
TM1-13c (R) -2- (4- (3- (4- acetylaminos phenoxy group) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) amino) Propyl acetate：White solid；m.p.:137-138℃；1H NMR(300MHz,CDCl3)δ:7.44-7.19(9H,m,Ar-H), 6.94-6.79 (4H, m, Ar-H), 5.85 (1H, d, J=6.9Hz, NH), 5.29 (1H, d, J=6.9Hz, * CH), 5.16-5.01 (2H,m,PhCH2-),4.16-3.95(6H,m,-OCH2-),2.30-2.19(2H,m,-CH2-),2.15(3H,s,-CH3), 1.65-1.50(2H,m,-CH2-), 0.82 (3H, t, J=7.5Hz ,-CH3)；13C NMR(151MHz,CDCl3)δ:171.19, 168.65,162.82,159.10,155.68,155.52,136.29,131.47,129.06,128.58,128.41,128.24, 128.16,121.96,114.97,114.89,77.37,77.16,76.95,67.42,67.14,64.77,64.62,57.59, 31.58,29.36,24.20,21.87；HRMS:C30H34N2O7[M+H]+Calculated value 535.2439, measured value 535.2446.
TM1-13d (R) -2- (4- (3- (4- acetylaminos phenoxy group) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) amino) Butyl acetate：White solid；m.p.:124-125℃；1H NMR(300MHz,CDCl3)δ:7.49-7.12(9H,m,Ar-H), 6.95-6.75 (4H, m, Ar-H), 5.85 (1H, d, J=6.0Hz, NH), 5.28 (1H, d, J=6.9Hz, * CH), 5.19-5.00 (2H,m,PhCH2-),4.26-3.95(6H,m,-OCH2-),2.31-2.18(2H,m,-CH2-),2.18-2.09(3H,s,- CH3), 1.54 (2H, t, J=6.6Hz ,-CH2-),1.30-1.19(2H,m,-CH2-), 0.85 (3H, t, J=7.2Hz ,-CH3) ；13C NMR(151MHz,CDCl3)δ:171.16,168.48,159.11,155.68,155.50,136.30,131.47, 129.07,128.59,128.41,128.24,128.17,121.95,114.98,114.90,77.37,77.16,76.95, 67.13,65.73,64.77,64.63,57.59,30.48,29.37,24.26,18.94,13.61；HRMS:C31H36N2O7[M+ Na]+Calculated value 571.2415, measured value 571.2418.
TM1-14a (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- Phenoxypropoxies) phenyl) methyl acetate：White Solid；m.p.:68-70℃；1H NMR(300MHz,CDCl3)δ:7.26-7.34(10H,m,Ar-H),6.87-6.97(4H,m, Ar-H), 5.78 (1H, d, J=6.3Hz, NH), 5.30 (1H, d, J=6.9Hz, * CH), 5.09 (2H, q, J=12.3Hz, 17.1Hz,PhCH2-),4.13-4.17(4H,m,-OCH2-),3.72(3H,s,-OCH3),2.21-2.29(2H,m,-CH2-)；13C NMR(75MHz,CDCl3)δ:171.1,158.7,158.3,154.9,135.7,129.1,128.1,128.0,127.8, 120.3,114.5,114.0,66.7,64.1,63.7,56.9,52.4,28.8；HRMS:C26H27NO6[M+Na]+Calculated value 472.1731, measured value 472.1743.
TM1-14b (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- Phenoxypropoxies) phenyl) ethyl acetate：White Solid；m.p.:97-99℃；1H NMR(300MHz,CDCl3)δ:7.44-7.07(9H,m,Ar-H),7.01-6.78(5H,m, ), Ar-H 5.80 (1H, d, J=6,9Hz, NH), 5.28 (1H, d, J=7.2Hz, * CH), 5.17-5.00 (2H, m, PhCH2-), 4.29-4.00(6H,m,-OCH2-),2.30-2.19(2H,m,-CH2-), 1.20 (3H, d, J=7.2Hz ,-CH3)；13C NMR (151MHz,CDCl3)δ:171.11,162.63,159.16,158.96,155.46,136.38,129.56,129.11, 128.61,128.48,128.25,120.90,115.01,114.66,77.37,77.16,76.95,67.14,64.68, 64.38,61.89,57.58,29.42,14.10；HRMS:C27H29NO6[M+Na]+Calculated value 486.1887, measured value 486.1891.
TM1-14c (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- Phenoxypropoxies) phenyl) propyl acetate：White Solid；m.p.:52-54℃；1H NMR(300MHz,CDCl3)δ:7.41-7.10(9H,m,Ar-H),7.00-6.90(5H,m, Ar-H),5.97-5.75(1H,m,NH),5.34-5.23(1H,m,*CH),5.16-5.02(2H,m,PhCH2-),4.20-3.99 (6H,m,-OCH2-),2.32-2.19(2H,m,-CH2-),1.66-1.52(2H,m,-CH2-), 0.82 (3H, t, J=7.2Hz ,- CH3)；13C NMR(151MHz,CDCl3)δ:171.20,159.14,158.96,155.47,136.38,129.56,129.19, 128.61,128.45,128.25,127.06,120.90,115.00,114.66,77.37,77.16,76.95,67.41, 67.14,64.70,64.39,57.59,29.42,21.92,10.23；HRMS:C28H31NO6[M+Na]+Calculated value 500.2044, Measured value 500.2046.
TM1-14d (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- Phenoxypropoxies) phenyl) butyl acetate：White Solid；m.p.:57-59℃；1H NMR(300MHz,CDCl3)δ:7.41-7.17(9H,m,Ar-H),7.02-6.91(5H,m, Ar-H),5.86-5.79(1H,m,NH),5.34-5.27(1H,m,*CH),5.18-5.04(2H,m,PhCH2-),4.23-4.00 (6H,m,-OCH2-),2.34-2.20(2H,m,-CH2-),1.62-1.50(2H,m,-CH2-),1.32-1.19(2H,m,- CH2-), 0.87 (3H, t, J=7.2Hz ,-CH3)；13C NMR(151MHz,CDCl3)δ:171.18,159.14,158.95, 155.45,136.37,129.55,129.17,128.60,128.44,128.23,127.04,120.89,114.99,114.66, 77.37,77.16,76.95,67.12,65.71,64.70,64.38,57.58,30.51,29.41,18.97,13.63.
TM1-15a (R) -2- (((benzyloxycarbonyl group) amino) -2- (4- (3- (naphthalene -2- bases epoxide) propoxyl group) phenyl) acetic acid Methyl esters：White solid；m.p.:87-88℃；1H NMR(300MHz,DMSO-d6)δ:8.22 (1H, d, J=7.5Hz, NH) .7.80 (3H, t, J=8.1Hz, Ar-H), 7.15-7.47 (11H, m, Ar-H), 6.96 (2H, d, J=8.7Hz, Ar-H), 5.20 (1H, D, J=7.5Hz, * CH), 5.05 (2H, s, PhCH2-),4.15-4.27(4H,m,-OCH2-),3.60(3H,s,-OCH3), 2.22-2.26(2H,m,-CH2-)；13C NMR(75MHz,DMSO-d6)δ:172.0,158.8,156.8,156.3,137.2, 134.7,129.7,129.7,129.6,128.9,128.8,128.7,128.3,128.2,127.9,127.1,126.8, 124.0,119.2,114.9,107.1,66.1,64.7,57.9,52.6,29.0；HRMS:C30H29NO6[M+Na]+Calculated value 522.1887, measured value 522.1890.
TM1-15b (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (naphthalene -2- bases epoxide) propoxyl group) phenyl) acetic acid second Ester：Yellow solid；m.p.:93-95℃；1H NMR(300MHz,CDCl3)δ:7.85-7.50(3H,m,Ar-H),7.49-6.97 (11H, m, Ar-H), 6.95-6.78 (2H, m, Ar-H), 5.78 (1H, d, J=6.6Hz, NH), 5.29 (1H, d, J=7.3Hz, * CH),5.15-4.99(2H,m,PhCH2-), 4.27 (2H, t, J=5.7Hz ,-OCH2-),4.22-4.05(2H,m,-OCH2-), 2.37-2.25(2H,m,-CH2-),1.22-1.09(3H,m,-CH3)；13C NMR(151MHz,CDCl3)δ:171.11, 159.17,158.96,156.93,155.46,136.38,134.70,129.52,129.16,128.62,128.51,128.26, 127.75,126.85,126.48,123.75,118.96,115.03,106.92,77.37,77.16,76.95,67.16, 64.72,64.56,61.91,57.59,29.40,14.11；HRMS:C31H31NO6[M+Na]+Calculated value 536.2044, measured value 536.2047.
TM1-15c (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (naphthalene -2- bases epoxide) propoxyl group) phenyl) acetic acid third Ester：Yellow solid；m.p.:90-92℃；1H NMR(300MHz,CDCl3)δ:7.82-7.60(3H,m,Ar-H),7.54-7.18 (9H, m, Ar-H), 5.80 (1H, d, J=5.4Hz, NH), 5.29 (1H, d, J=6.3Hz, * CH), 5.16-5.00 (2H, m, PhCH2-),4.37-3.91(6H,m,-OCH2-), 2.32 (2H, t, J=5.1Hz ,-CH2-),1.35-1.11(2H,m,- CH2-),0.85-0.75(3H,m,-CH3)；13C NMR(151MHz,CDCl3)δ:171.20,159.16,158.95,156.94, 155.47,136.38,134.71,129.53,129.24,129.17,128.63,128.49,128.27,127.76,126.86, 126.49,123.76,118.96,115.03,106.94,77.37,77.16,76.95,67.47,67.45,67.17,64.75, 64.58,57.60,32.45,29.41,21.94；HRMS:C32H33NO6[M+Na]+Calculated value 550.2200, measured value 550.2204.
TM1-15d (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (naphthalene -2- bases epoxide) propoxyl group) phenyl) acetic acid fourth Ester：Yellow solid；m.p.:68-70℃；1H NMR(300MHz,CDCl3)δ:7.81-7.63(3H,m,Ar-H),7.49-7.21 (9H, m, Ar-H), 7.14 (2H, d, J=7.2Hz, Ar-H), 6.90 (2H, d, J=8.4Hz, Ar-H), 5.82 (1H, d, J= 6.9Hz, NH), 5.28 (1H, d, J=7.2Hz, * CH), 5.10-5.00 (2H, m, PhCH2-), 4.27 (2H, t, J=6.0Hz ,- OCH2-), 4.19 (2H, t, J=6.0Hz ,-OCH2-), 4.09 (2H, t, J=9.3Hz ,-OCH2-), 2.32 (2H, t, J= 6.0Hz,-CH2-),1.60-1.45(2H,m,-CH2-),1.27-1.21(2H,m,-CH2-), 0.84 (3H, t, J=4.2Hz ,- CH3)；13C NMR(151MHz,CDCl3)δ:171.18,162.63,159.13,156.91,155.47,136.36,134.68, 129.50,129.20,129.14,128.60,128.46,128.24,127.73,126.83,126.46,123.73,118.93, 115.00,106.92,77.37,77.16,76.95,67.13,65.72,64.73,64.55,57.59,30.50,29.37, 18.97,13.62；HRMS:C33H35NO6[M+Na]+Calculated value 564.2357, measured value 564.2361.
TM1-16a (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- ((2- oxo -2H- chromene -4- bases) epoxide) third oxygen Base) phenyl) methyl acetate：White solid；m.p.:120-122℃；1H NMR(300MHz,CDCl3)δ:7.80 (2H, d, J= 7.8Hz, Ar-H), 7.56 (1H, t, J=8.4Hz, Ar-H), 7.24-7.34 (8H, m, Ar-H), 6.89 (2H, d, J=8.4Hz, ), Ar-H 5.79 (1H, d, J=6.6Hz, NH), 5.72 (1H, s, COCH-), 5.31 (1H, d, J=7.2Hz, * CH), 5.08 (2H, d, J=6.0Hz, PhCH2-),4.17-4.34(4H,m,-OCH2-),3.71(3H,s,-OCH3),2.35-2.43(2H, m,-CH2-)；13C NMR(75MHz,CDCl3)δ:171.0,165.0,162.4,158.3,154.9,152.9,135.7, 132.0,128.7,128.1,127.8,127.7,123.5,122.5,116.4,115.2,114.4,90.3,66.6,65.4, 63.4,56.9,52.4,28.1；HRMS:C29H27NO8[M+Na]+Calculated value 540.1629, measured value 540.1627.
TM1-16b (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- ((2- oxo -2H- chromene -4- bases) epoxide) third oxygen Base) phenyl) ethyl acetate：White solid；m.p.:127-128℃；1H NMR(300MHz,CDCl3)δ:7.80 (1H, d, J= 7.8Hz, Ar-H), 7.62-7.49 (1H, m, Ar-H), 7.41-7.08 (9H, m, Ar-H), 6.89 (2H, d, J=8.4Hz, Ar- ), H 5.81 (1H, d, J=6.9Hz, NH), 5.72 (1H, s, COCH-), 5.28 (1H, d, J=7.2Hz, * CH), 5.15-5.00 (2H,m,PhCH2-), 4.34 (2H, t, J=6.0Hz ,-OCH2-),4.26-4.02(4H,m,-OCH2-),2.47-2.31(2H, m,-CH2-), 1.20 (3H, t, J=6.9Hz ,-CH3)；13C NMR(151MHz,CDCl3)δ:171.00,165.51,162.82, 158.79,155.43,153.48,136.32,132.50,129.54,128.59,128.55,128.25,128.20,123.95, 122.99,116.90,115.77,114.93,90.82,77.37,77.16,76.95,67.13,66.02,64.06,61.92, 57.53,28.69,14.08；HRMS:C30H29NO8[M+Na]+Calculated value 554.1785, measured value 554.1790.
TM1-16c (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- ((2- oxo -2H- chromene -4- bases) epoxide) third oxygen Base) phenyl) propyl acetate：White solid；m.p.:142-144℃；1H NMR(300MHz,CDCl3)δ:7.80 (1H, d, J= 7.5Hz, Ar-H), 7.60-7.51 (1H, m, Ar-H), 7.41-7.14 (9H, m, Ar-H), 6.88 (2H, d, J=8.4Hz, Ar- ), H 5.83 (1H, d, J=6.9Hz, NH), 5.72 (1H, s, COCH-), 5.29 (1H, d, J=7.2Hz, * CH), 5.16-5.00 (2H,m,PhCH2-), 4.34 (2H, t, J=5.7Hz ,-OCH2-), 4.19 (2H, t, J=5.7Hz ,-OCH2-),4.12-3.99 (2H,m,-OCH2-)2.45-2.32(2H,m,-CH2-),1.61-1.51(2H,m,-CH2-), 0.82 (3H, t, J=8.7Hz ,- CH3)；13C NMR(151MHz,CDCl3)δ:171.07,165.50,162.82,158.77,155.43,153.48,136.32, 132.49,129.61,128.58,128.52,128.23,128.19,123.95,122.98,116.90,115.77,114.91, 90.82,77.37,77.16,76.95,67.43,67.12,66.03,64.07,57.53,28.69,21.89,10.20；HRMS: C31H31NO8[M+Na]+Calculated value 568.1942, measured value 568.1945.
TM1-16d (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- ((2- oxo -2H- chromene -4- bases) epoxide) third oxygen Base) phenyl) butyl acetate：White solid；m.p.:122-125℃；1H NMR(300MHz,CDCl3)δ:7.80 (1H, d, J= 4.8Hz, Ar-H), 7.61-7.48 (1H, m, Ar-H), 7.41-7.13 (9H, m, Ar-H), 6.98 (2H, d, J=8.7Hz, Ar- ), H 5.83 (1H, d, J=6.9Hz, NH), 5.72 (1H, s, COCH-), 5.29 (1H, d, J=7.2Hz, * CH), 5.17-4.99 (2H,m,PhCH2-), 4.34 (2H, t, J=6.0Hz ,-OCH2-),4.22-3.99(4H,m,-OCH2-),2.47-2.32(2H, m,-CH2-),1.59-1.46(2H,m,-CH2-),1.2-1.19(2H,m,-CH2-), 0.84 (3H, t, J=7.5Hz ,-CH3)；13C NMR(151MHz,CDCl3)δ:171.08,165.52,162.83,158.79,155.44,153.50,136.33, 132.51,129.63,128.60,128.53,128.26,128.22,123.96,122.99,116.92,115.78,114.93, 90.84,77.37,77.16,76.95,67.14,66.03,65.77,64.09,57.55,30.50,28.70,18.97, 13.62；HRMS:C32H33NO8[M+Na]+Calculated value 582.2098, measured value 582.2103.
TM1-17a (R) -2- (4- (3- (benzo [d] oxazole -2- bases sulfenyl) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) ammonia Base) methyl acetate：White solid；m.p.:101-103℃；1H NMR(300MHz,DMSO-d6)δ:8.22 (1H, d, J= 7.5Hz, NH), 7.30-7.36 (11H, m, Ar-H), 6.94 (2H, d, J=8.7Hz, Ar-H), 5.20 (1H, d, J=7.2Hz, * CH),5.05(2H,s,PhCH2-), 4.11 (2H, t, J=6.0Hz ,-OCH2-),3.60(3H,s,-OCH3),3.48(2H,t,J =6.9Hz ,-SCH2-),2.21-2.29(2H,m,-CH2-)；13C NMR(75MHz,DMSO-d6)δ:171.6,164.2, 158.3,155.9,151.2,141.3,136.9,129.2,128.4,128.3,127.9,127.8,124.6,124.2, 118.2,114.5,110.2,65.8,65.7,57.4,52.2,28.6,28.5；HRMS:C27H26N2O6S[M+Na]+Calculated value 529.1404, measured value 529.1410.
TM1-17b (R) -2- (4- (3- (benzo [d] oxazole -2- bases sulfenyl) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) ammonia Base) ethyl acetate：White solid；m.p.:89-91℃；1H NMR(300MHz,CDCl3)δ:7.60 (1H, d, J=7.2Hz, Ar- ), H 7.22-7.44 (10H, m, Ar-H), 6.88 (2H, d, J=8.7Hz, Ar-H), 5.78 (1H, d, J=6.6Hz, NH), 5.29 (1H, d, J=7.2Hz, * CH), 5.10 (2H, q, J=12.3Hz, 18.0Hz, PhCH2-),4.11-4.20(4H,m,-OCH2- and-SCH2-),3.51(2H,m,-OCH2-),2.31-2.39(2H,m,-CH2-), 1.21 (3H, t, J=6.9Hz ,-CH3)；13C NMR(75MHz,DMSO-d6)δ:170.6,164.2,158.4,154.9,151.4,141.4,135.7,128.7,128.1, 128.0,127.8,123.9,123.5,118.0,114.6,114.4,109.5,66.6,65.3,61.5,57.0,28.5, 28.5,13.6；HRMS:C28H28N2O6S[M+Na]+Calculated value 543.1560, measured value 543.1565.
TM1-17c (R) -2- (4- (3- (benzo [d] oxazole -2- bases sulfenyl) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) ammonia Base) propyl acetate：White solid；m.p.:97-98℃；1H NMR(300MHz,CDCl3)δ:7.62-7.49(1H,m,Ar-H), 7.44-7.09(10H,m,Ar-H),6.90-6.77(2H,m,Ar-H),5.93-5.69(1H,m,NH),5.32-5.20(1H, m,*CH),5.15-4.97(2H,m,PhCH2-),4.14-3.93(4H,m,OCH2-and COCH2-), 3.46 (2H, t, J= 2.9Hz,SCH2-),2.39-2.22(2H,m,-CH2-),1.63-1.47(2H,m,-CH2-),0.83-0.70(3H,m,-CH3) ；13C NMR(75MHz,CDCl3)δ:171.18,164.74,158.90,155.42,151.93,128.64,128.48, 128.31,128.28,126.83,124.42,124.02,118.48,114.89,109.98,77.58,77.16,76.74, 67.46,67.16,65.79,57.50,29.06,28.98,21.90,10.27；HRMS:C29H30N2O6S[M+H]+Calculated value 535.1897, measured value 535.1901.
TM1-17d (R) -2- (4- (3- (benzo [d] oxazole -2- bases sulfenyl) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) ammonia Base) butyl acetate：White solid；m.p.:86-88℃；1H NMR(300MHz,CDCl3)δ:7.68 (1H, d, J=7.2Hz, Ar- ), H 7.42 (1H, d, J=7.8Hz, Ar-H), 7.40-7.10 (9H, m, Ar-H), 6.93-6.91 (2H, m, Ar-H), 5.98- 5.73(1H,m,NH),5.35-5.23(1H,m,*CH),5.17-5.02(2H,m,PhCH2-),4.21-4.00(4H,m,-OCH2- and COCH2-), 3.50 (2H, t, J=2.9Hz ,-SCH2-),3.41-2.28(2H,m,-CH2-),1.61-1.46(2H,m,- CH2-),1.31-1.17(2H,m,-CH2-), 0.95-0.79 (3H, t, J=7.2Hz ,-CH3)；13C NMR(75MHz,CDCl3) δ:171.16,164.71,158.89,155.41,151.92,129.27,128.60,128.45,128.26,124.39, 123.99,118.47,114.89,109.95,77.58,77.16,76.74,67.13,65.81,65.75,57.50,30.46, 29.07,28.97,18.96,13.67；HRMS:C30H32N2O6S[M+H]+Calculated value 549.2054, measured value 549.2058.
TM1-18a (R) -2- (4- (3- ((1H- benzos [d] imidazoles -2- bases) sulfenyl) propoxyl group) phenyl) -2- ((benzyloxy carbonyls Base) amino) methyl acetate：White solid；m.p.:95-96℃；1H NMR(300MHz,CDCl3)δ:7.18-7.48(11H,m, ), Ar-H 6.82 (2H, d, J=8.4Hz, Ar-H), 5.84 (1H, d, J=6.3Hz, NH), 5.28 (1H, d, J=6.6Hz, * ), CH 5.10 (2H, q, J=12.3Hz, 18.3Hz, PhCH2-),4.09-4.19(4H,m,-OCH2-and-SCH2-),3.71 (1H,s,NH),3.49(3H,s,-OCH3),2.24-2.27(2H,m,-CH2-)；13C NMR(75MHz,CDCl3)δ:170.6, 158.4,155.2,149.8,135.6,128.3,128.1,128.0,127.9,127.9,127.7,121.8,114.4, 114.4,66.8,65.3,61.6,57.1,52.4,28.8.
TM1-18b (R) -2- (4- (3- ((1H- benzos [d] imidazoles -2- bases) sulfenyl) propoxyl group) phenyl) -2- ((benzyloxy carbonyls Base) amino) ethyl acetate：White solid；m.p.:96-97℃；1H NMR(300MHz,CDCl3)δ:7.18-7.51(11H,m, ), Ar-H 6.82 (2H, d, J=8.4Hz, Ar-H), 5.85 (1H, d, J=6.9Hz, NH), 5.28 (1H, d, J=7.2Hz, * ), CH 5.10 (2H, q, J=12.3Hz, 18.3Hz, PhCH2-),4.06-4.21(5H,m,-OCH2-,-SCH2-and NH), 3.50-3.52(2H,m,-OCH2-),2.24-2.28(2H,m,-CH2-), 1.20 (3H, t, J=6.9Hz ,-CH3)；13C NMR (75MHz,CDCl3)δ:170.6,158.3,155.1,149.7,135.6,128.1,127.9,127.7,121.9,114.3, 113.6,66.7,65.3,61.5,57.1,28.8,28.7,13.6；HRMS:C28H29N3O5S[M+Na]+Calculated value 542.1720, Measured value 542.1723.
TM1-18c (R) -2- (4- (3- ((1H- benzos [d] imidazoles -2- bases) sulfenyl) propoxyl group) phenyl) -2- ((benzyloxy carbonyls Base) amino) propyl acetate：Yellow oil；1H NMR(300MHz,CDCl3)δ:7.54-7.45(2H,m,Ar-H),7.38- 7.13 (9H, m, Ar-H), 6.94-6.74 (2H, m, Ar-H), 5.91 (1H, d, J=9Hz, NH), 5.28 (1H, d, J=9Hz, * CH),5.17-5.00(2H,m,PhCH2-),4.14-3.97(4H,m,-OCH2-and COCH2-), 3.48 (2H, t, J= 7.5Hz,-SCH2-),2.27-2.18(2H,m,-CH2-),1.65-1.49(3H,m,-CH2-), 0.81 (3H, t, J=7.2Hz ,- CH3)；13C NMR(151MHz,CDCl3)δ:171.07,158.77,155.58,150.03,138.54,136.13,129.04, 128.53,128.32,128.21,128.09,122.65,114.84,114.03,77.28,77.07,76.86,67.42, 67.17,65.83,57.55,29.31,29.23,21.79,10.11；HRMS:C29H31N3O5S[M+H]+Calculated value 534.2057, Measured value 534.2060.
TM1-18d (R) -2- (4- (3- ((1H- benzos [d] imidazoles -2- bases) sulfenyl) propoxyl group) phenyl) -2- ((benzyloxy carbonyls Base) amino) butyl acetate：Yellow solid；m.p.:105-107℃；1H NMR(300MHz,CDCl3)δ:7.55-7.42(2H,m, Ar-H),7.41-7.11(9H,m,Ar-H),6.86-6.75(2H,m,Ar-H),5.93-5.79(1H,m,NH),5.33-5.22 (1H,m,*CH),5.17-5.00(2H,m,PhCH2-),4.21-3.93(4H,m,-OCH2-),3.56-3.41(2H,m, SCH2-),2.33-2.16(2H,m,-CH2-),1.61-1.45(2H,m,-CH2-),1.29-1.14(2H,m,-CH2-),0.85 (3H, t, J=7.5Hz ,-CH3)；13C NMR(75MHz,CDCl3)δ:171.12,158.75,155.60,150.18,139.42, 136.05,128.77,128.54,128.31,128.24,128.11,122.24,114.72,114.09,77.58,77.16, 76.74,67.16,65.74,57.55,30.33,29.17,18.86,13.59；HRMS:C30H33N3O5S[M+H]+Calculated value 548.2214, measured value 548.2217.
TM1-19a (R) -2- (4- (3- ((5- amino -1,3,4- thiadiazoles -2- bases) sulfenyl) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) amino) methyl acetate：Yellow oil；1H NMR(300MHz,CDCl3)δ:7.34-7.27(7H,m,Ar- ), H 6.85 (2H, d, J=8.4Hz, Ar-H), 5.96 (1H, d, J=6.6Hz, NH), 5.30 (1H, s, * CH), 5.13-5.04 (2H,m,PhCH2-),4.13-4.07(2H,m,-OCH2-),3.71(3H,s,-CH3),3.40-3.28(2H,m,SCH2-), 2.22-2.18(2H,m,-CH2-)；13C NMR(75MHz,CDCl3)δ:171.56,167.15,158.80,156.33, 155.49,136.15,128.84,128.60,128.53,128.30,128.20,114.99,67.18,65.60,57.43, 52.92,29.77,14.27.
TM1-19b (R) -2- (4- (3- ((5- amino -1,3,4- thiadiazoles -2- bases) sulfenyl) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) amino) ethyl acetate：White solid；m.p.:87-90℃；1H NMR(300MHz,CDCl3)δ:7.34-7.26 (7H, m, Ar-H), 6.85 (2H, d, J=8.4Hz, Ar-H), 5.95 (1H, d, J=6.6Hz, NH), 5.27 (1H, d, J= 6.9Hz,*CH),5.14-5.04(2H,m,PhCH2-),4.22-4.06(4H,m,-OCH2-and COCH2-),3.30(2H,t,J =6.9Hz, SCH2-),2.22-2.18(2H,m,-CH2-), 1.20 (3H, t, J=7.2Hz ,-CH3)；13C NMR(75MHz, CDCl3)δ:171.09,158.76,155.50,136.16,128.94,128.60,128.46,128.29,128.19, 114.93,67.14,65.61,62.00,57.52,31.58,29.05,14.08；HRMS:C23H26N4O5S2[M+H]+Calculated value 503.1417, measured value 503.1420.
TM1-19c (R) -2- (4- (3- ((5- amino -1,3,4- thiadiazoles -2- bases) sulfenyl) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) amino) propyl acetate：White solid；m.p.:59-61℃；1H NMR(600MHz,DMSO)δ:8.14(1H, D, J=7.8Hz, NH), 7.41-7.27 (9H, m, Ar-H), 6.93-6.99 (2H, d, J=9.0Hz, NH2),5.19-5.16 (1H,m,*CH),5.09-5.02(2H,m,PhCH2-), 4.06 (3H, t, J=6.0Hz ,-OCH2-), 3.99 (2H, t, J= 6.6Hz,COCH2-), 3.19 (2H, t, J=6.6Hz ,-SCH2-),2.10-2.04(2H,m,-CH2-),1.54-1.46(2H, m,-CH2-), 0.77 (3H, t, J=4.2Hz ,-CH3)；HRMS:C24H28N4O5S2[M+H]+Calculated value 517.1574, measured value 517.1580.
TM1-19d (R) -2- (4- (3- ((5- amino -1,3,4- thiadiazoles -2- bases) sulfenyl) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) amino) butyl acetate：White solid；m.p.:84-89℃；1H NMR(300MHz,CDCl3)δ:7.41-7.17 (7H, m, Ar-H), 6.90-6.77 (2H, m, Ar-H), 5.94 (1H, d, J=6.6Hz, NH), 5.27 (1H, d, J=6.9Hz, * CH),5.15-5.01(2H,m,PhCH2-),4.20-4.02(4H,m,-OCH2-and COCH2-), 3.30 (2H, t, J= 6.9Hz,SCH2-), 2.21 (2H, t, J=6.0Hz ,-CH2-),1.60-1.45(2H,m,-CH2-),1.34-1.14(2H,m,- CH2-), 0.85 (3H, t, J=7.2Hz ,-CH3)；13C NMR(75MHz,CDCl3)δ:171.17,158.77,155.49, 136.17,129.04,128.62,128.42,128.30,128.21,114.94,77.58,77.16,76.74,67.16, 65.81,65.64,57.53,31.59,30.42,29.08,18.94,13.68；HRMS:C25H30N4O5S2[M+Na]+Calculated value 553.1550, measured value 553.1554.
TM1-20a (R) -2- (4- (3- ((4- hydroxyl -6- aminopyrimidine -2- bases) sulfenyl) propoxyl group) phenyl) -2- ((benzyls Oxygen carbonyl) amino) methyl acetate：White solid；m.p.:81-84℃；1H NMR(300MHz,CDCl3)δ:7.42-7.12(7H, m,Ar-H),6.91-6.81(2H,m,Ar-H),5.95-5.86(1H,m,NH),5.33-5.25(1H,m,*CH),5.15(1H, s,Ar-H),5.12-5.00(2H,m,PhCH2-), 4.56 (1H, s, OH), 4.06 (2H, t, J=5.4Hz, OCH2),3.72(3H, s,-CH3), 3.28 (2H, t, J=6.9Hz ,-SCH2-),2.24-2.11(2H,m,-CH2-)；13C NMR(75MHz,CDCl3)δ: 171.60,166.18,163.23,161.39,158.89,155.53,136.14,128.65,128.56,128.52,128.24, 128.14,114.86,83.62,77.59,77.16,76.74,67.11,65.87,57.43,52.85,28.98,26.89； HRMS:C24H26N4O6S[M+H]+Calculated value 499.1646, measured value 499.1650.
TM1-20b (R) -2- (4- (3- ((4- hydroxyl -6- aminopyrimidine -2- bases) sulfenyl) propoxyl group) phenyl) -2- ((benzyls Oxygen carbonyl) amino) ethyl acetate：White solid；m.p.:76-83℃；1H NMR(300MHz,CDCl3)δ:7.34-7.26(7H, M, Ar-H), 6.86 (2H, d, J=8.1Hz, Ar-H), 5.92 (1H, d, J=6.9Hz, NH), 5.26 (1H, d, J=6.9Hz, * CH),5.14(1H,s,Ar-H),5.10-5.03(2H,m,PhCH2-),4.54(1H,s,OH),4.21-4.10(2H,m, COCH2-), 4.06 (2H, t, J=5.7Hz, OCH2),3.34-3.22(2H,m,-SCH2-),2.24-2.10(2H,m,-CH2-), 1.20 (3H, t, J=7.2Hz ,-CH3)；13C NMR(151MHz,CDCl3)δ:171.05,166.20,163.18,161.56, 158.93,155.54,136.29,129.08,128.61,128.49,128.27,128.18,114.93,83.77,77.37, 77.16,76.95,67.15,65.96,61.97,57.58,29.13,27.03,14.09；HRMS:C25H28N4O6S[M+H]+Meter Calculation value 513.1802, measured value 513.1807.
TM1-20c (R) -2- (4- (3- ((4- hydroxyl -6- aminopyrimidine -2- bases) sulfenyl) propoxyl group) phenyl) -2- ((benzyls Oxygen carbonyl) amino) propyl acetate：Yellow oil；1H NMR(300MHz,CDCl3)δ:7.39-7.21(7H,m,Ar-H), 7.00-6.91(2H,m,Ar-H),6.00-5.94(1H,m,NH),5.22(1H,s,OH),5.30-5.24(1H,m,*CH), 5.15-5.00(3H,m,Ar-H and PhCH2-),4.12-3.99(4H,m,-OCH2-and COCH2-), 3.27 (2H, t, J= 5.4Hz,-SCH2-),2.22-2.11(2H,m,-CH2-),1.63-1.52(2H,m,-CH2-),0.94-0.80(3H,m,- CH3)；13C NMR(75MHz,CDCl3)δ:171.14,166.23,163.18,161.44,158.83,155.51,136.18, 129.02,128.60,128.44,128.27,128.19,114.79,83.67,77.58,77.16,76.74,67.46, 67.12,65.82,57.49,29.76,29.06,21.84,10.24；HRMS:C26H30N4O6S[M+H]+Calculated value 527.1959, Measured value 527.1962.
TM1-20d (R) -2- (4- (3- ((4- hydroxyl -6- aminopyrimidine -2- bases) sulfenyl) propoxyl group) phenyl) -2- ((benzyls Oxygen carbonyl) amino) butyl acetate：Yellow oil；1H NMR(300MHz,CDCl3)δ:7.43-7.12(7H,m,Ar-H), 6.92-6.79(2H,m,Ar-H),5.97-5.87(1H,m,NH),5.32-5.21(1H,m,*CH),5.14(1H,s,Ar-H), 5.12-5.00(2H,m,PhCH2-),5.52(1H,s,OH),4.20-3.97(4H,m,-OCH2-and COCH2-),3.37- 3.20(2H,m,-SCH2-),2.25-2.10(2H,m,-CH2-),1.61-1.46(2H,m,-CH2-),1.32-1.16(2H,m,- CH2-), 0.85 (3H, t, J=7.2Hz ,-CH3)；13C NMR(75MHz,CDCl3)δ:171.12,166.24,163.17, 161.46,158.86,155.50,136.20,129.07,128.61,128.44,128.28,128.20,114.83,111.54, 83.78,77.58,76.73,67.14,65.80,57.51,30.43,29.76,29.11,26.92,18.94,13.66；HRMS: C27H32N4O6S[M+H]+Calculated value 541.2115, measured value 541.2120.
The synthesis of the compound TM2 of embodiment 4
TM1-18 is added in round-bottomed flask, after being dissolved with q. s. methylene chloride (DCM), 2 times of m-chloros of mole is added Benzoyl hydroperoxide (mCPBA), stirred at ambient temperature reaction, TLC monitoring reaction process.After reaction terminates, concentration, silica gel column layer Analysis, obtains final product purpose compound TM2.
The compound TM2 generated datas of table four
TM2-a (R) -2- (4- (3- ((1H- benzos [d] imidazoles -2- bases) sulfonyl) propoxyl group) phenyl) -2- ((benzyloxy carbonyls Base) amino) methyl acetate：White solid；m.p.:96-97℃；1H NMR(300MHz,CDCl3)δ:2.32(m,2H,-CH2-), 3.70(s,3H,OCH3),4.02-4.20(m,5H,SCH2,NH,OCH2), 5.09 (q, 2H, J=12.0Hz, 13.8Hz, PhCH2), 5.27 (d, 1H, J=6.3Hz, * CH), 5.87 (d, 1H, J=6.3Hz, CONH), 6.76 (m, 2H, Ar-H), 7.21- 7.45(m,9H,Ar-H),7.75(m,2H,Ar-H)；13C NMR(75MHz,CDCl3)δ:22.2,51.8,57.0,61.6, 64.8,66.8,114.3,114.4,127.7,127.8,128.0,128.1,128.1,135.6,146.7,155.2,157.9, 170.7.
TM2-b (R) -2- (4- (3- ((1H- benzos [d] imidazoles -2- bases) sulfonyl) propoxyl group) phenyl) -2- ((benzyloxy carbonyls Base) amino) ethyl acetate：White solid；m.p.:98-99℃；1H NMR(300MHz,DMSO-d6)δ:1.20 (t, 3H, J= 6.9Hz,CH3),2.34(m,2H,-CH2-),3.71(m,2H,-CH2-),4.04-4.15(m,5H,SCH2,NH,OCH2),5.09 (d, 2H, J=5.1Hz, PhCH2), 5.27 (d, 1H, J=6.9Hz, * CH), 5.84 (d, 1H, J=6.9Hz, CONH), 6.77 (d, 2H, J=8.1Hz, Ar-H), 7.22-7.73 (m, 11H, Ar-H)；13C NMR(75MHz,CDCl3)δ:13.6,22.2, 29.3,51.7,57.0,61.6,64.7,66.7,114.3,125.1,127.7,127.8,128.0,128.1,128.8, 135.6,146.6,155.0,157.9,170.6.
TM2-c (R) -2- (4- (3- ((1H- benzos [d] imidazoles -2- bases) sulfonyl) propoxyl group) phenyl) -2- ((benzyloxy carbonyls Base) amino) propyl acetate：Yellow oil；1H NMR(300MHz,CDCl3)δ:8.00-7.65(2H,m,Ar-H),7.47- 7.09(9H,m,Ar-H),6.83-6.71(2H,m,Ar-H),5.93-5.90(1H,m,NH),5.32-5.25(1H,m,*CH), 5.16-5.00(2H,m,PhCH2),4.14-3.95(4H,m,OCH2and COCH2), 3.69 (2H, t, J=7.5Hz, SCH2), 2.40-2.26(2H,m,-CH2-),1.63-1.51(2H,m,-CH2-), 0.81 (3H, t, J=7.5Hz ,-CH3)；13C NMR (151MHz,CDCl3)δ:171.20,163.10,158.51,155.63,147.46,136.24,129.45,128.59, 128.46,128.26,128.17,125.26,120.43,114.90,77.37,77.16,76.95,67.50,67.22, 65.40,57.56,52.20,22.72,21.86,10.19；HRMS:C29H31N3O7S[M+Na]+Calculated value 588.1775, actual measurement Value 588.1780.
TM2-d (R) -2- (4- (3- ((1H- benzos [d] imidazoles -2- bases) sulfonyl) propoxyl group) phenyl) -2- ((benzyloxy carbonyls Base) amino) butyl acetate：White solid；m.p.:111-112℃；1H NMR(300MHz,CDCl3)δ:7.78-7.67(2H,s, Ar-H),7.49-7.40(2H,m,Ar-H),7.39-7.15(7H,m,Ar-H),6.91-6.71(2H,m,Ar-H),5.90- 5.82(1H,m,NH),5.32-5.24(1H,m,*CH),5.15-5.03(2H,m,PhCH2),4.19-3.98(4H,m,OCH2and COCH2),3.76-3.65(2H,m,-SCH2-),2.40-2.24(2H,m,-CH2-),1.60-1.44(2H,m,-CH2-), 1.31-1.15(2H,m,-CH2-), 0.84 (3H, t, J=6Hz ,-CH3)；13C NMR(75MHz,CDCl3)δ:171.27, 158.44,155.68,155.65,147.22,136.13,129.31,128.63,128.47,128.33,128.22,127.87, 125.41,114.79,77.58,77.16,76.74,67.28,65.90,65.26,57.52,52.21,30.42,22.67, 18.94,13.67；HRMS:C30H33N3O7S[M+H]+Calculated value 580.2112, measured value 580.2116.
The synthesis of the compound TM3 of embodiment 5
TM1 is added in round-bottomed flask, after being dissolved with 1-3mL tetrahydrofurans (THF), 1N LiOH is added dropwise, under environment temperature (15-35 DEG C) stirring reaction, TLC monitoring reaction process.After reaction terminates (about 2h), 1N HCl regulation pH=7, decompression rotation is added dropwise Tetrahydrofuran is evaporated off, 1N HCl regulation pH=5 are added dropwise, reaction solution is muddy, gradually obtains viscous solid, ethyl acetate (10mL) Extraction, collects organic phase, washing, anhydrous Na2SO4Dry, suction filtration, filtrate decompression revolving removes solvent, obtains stickiness product, plus Precipitation solid is freezed after entering ether, suction filtration obtains purpose compound TM3.
The compound TM3 generated datas of table five
TM3-1 (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (3- formvlphenoxvs) propoxyl group) phenyl) acetic acid： White solid；m.p.:85-87℃；1H NMR(300MHz,DMSO-d6)δ:2.17-2.21(m,2H,-CH2-),4.12-4.23 (m,4H,2-OCH2),5.04(s,2H,PhCH2), 5.09 (d, 1H, J=8.4Hz, * CH), 6.94 (d, 2H, J=8.7Hz, Ar- ), H 7.30-7.52 (m, 11H, Ar-H), 8.06 (d, 1H, J=8.1Hz, CONH), 12.76 (s, 1H, COOH)；13C NMR (75MHz,DMSO-d6)δ:28.5,57.5,64.2,64.6,65.6,113.7,114.4,121.4,127.8,128.4, 129.1,130.4,136.9,137.6,155.8,158.2,159.0,172.4,193.0；HRMS:C26H25NO7[M+Na]+Calculate Value 486.1523, measured value 486.1528.
TM3-2 (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (2- formvlphenoxvs) propoxyl group) phenyl) acetic acid： Yellow oil；1H NMR(300MHz,DMSO-d6)δ:2.22-2.26(m,2H,-CH2-),4.17-4.31(m,4H,2- OCH2),5.05(s,2H,PhCH2), 5.09 (d, 1H, J=8.1Hz, * CH), 6.94 (d, 2H, J=8.1Hz, Ar-H), 7.08 (t, 1H, J=7.5Hz, Ar-H), 7.24-7.70 (m, 10H, Ar-H), 8.06 (d, 1H, J=7.8Hz, CONH), 12.71 (s, 1H,COOH)；13C NMR(75MHz,DMSO-d6)δ:28.5,57.5,64.3,65.2,65.6,113.4,114.3,120.7, 124.3,127.7,127.8,127.9,128.3,129.0,129.1,136.4,137.0,155.8,158.2,160.9, 172.4,189.3；HRMS:C26H25NO7[M+Na]+Calculated value 486.1523, measured value 486.1527.
TM3-3 (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (4- formvlphenoxvs) propoxyl group) phenyl) acetic acid： White solid；m.p.:156-158℃；1H NMR(300MHz,DMSO-d6)δ:2.18-2.22(m,2H,-CH2-),4.11- 4.25(m,4H,2-OCH2),5.04(s,2H,PhCH2), 5.09 (d, 1H, J=8.1Hz, * CH), 6.93 (d, 2H, J=8.4Hz, ), Ar-H 7.14 (d, 2H, J=8.7Hz, Ar-H), 7.30-7.35 (m, 7H, Ar-H), 7.86 (d, 2H, J=8.7Hz, Ar-H), 8.05 (d, 1H, J=8.1Hz, CONH), 9.86 (s, 1H, CHO), 12.75 (s, 1H, COOH)；13C NMR(75MHz,DMSO- d6)δ:28.4,57.4,64.1,64.8,65.5,109.5,109.7,114.4,115.0,121.9,123.8,127.8, 127.9,128.4,129.0,129.1,129.7,131.9,136.9,155.8,158.1,163.5,172.4,191.4；HRMS: C26H25NO7[M+Na]+Calculated value 486.1523, measured value 486.1527.
TM3-4 (R) -4- (3- (4- (((benzyloxycarbonyl group) amino) (carboxyl) methyl) phenoxy group) propoxyl group) benzoic acid：In vain Color solid；m.p.:178-180℃；1H NMR(300MHz,DMSO-d6)δ:2.16-2.20(m,2H,-CH2-),4.12(t,2H, J=6.0Hz, OCH2), 4.19 (t, 2H, J=6.0Hz, OCH2),5.07(t,3H,PhCH2, * CH), 6.93 (d, 2H, J= 8.4Hz, Ar-H), 7.04 (d, 2H, J=9.0Hz, Ar-H), 7.29-7.35 (m, 6H, Ar-H), 7.88 (d, 2H, J=8.7Hz, ), Ar-H 8.00 (d, 1H, J=8.1Hz, CONH)；13C NMR(75MHz,DMSO-d6)δ:28.5,57.6,64.2,64.6, 65.6,114.3,114.4,123.0,127.7,127.8,128.4,129.0,129.4,131.4,136.9,155.8,158.1, 162.1,167.1,172.4；HRMS:C26H25NO8[M+Na]+Calculated value 502.1472, measured value 502.1479.
TM3-5 (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (4- (carboxymethyl) phenoxy group) propoxyl group) phenyl) second Acid：White solid；m.p.:138-140℃；1H NMR(300MHz,DMSO-d6)δ:2.13-2.15(m,2H,-CH2-),3.48 (s,2H,COCH2-),4.10-4.12(m,4H,2-OCH2),5.04(s,2H,PhCH2), 5.09 (d, 1H, J=7.8Hz, * CH), 6.87-6.90 (m, 4H, Ar-H), 7.16 (d, 2H, J=8.4Hz, Ar-H), 7.30-7.36 (m, 7H, Ar-H), 8.06 (d, 1H, J=7.8Hz, CONH), 12.48 (s, 2H, COOH)；13C NMR(75MHz,DMSO-d6)δ:28.6,39.8,57.5,64.1, 64.3,65.6,114.2,114.4,127.1,127.8,127.8,128.4,129.1,130.4,137.0,155.8,157.3, 158.2,172.4,173.0.
TM3-6 (R) -3- (4- (3- (4- (((benzyloxycarbonyl group) amino) (carboxyl) methyl) phenoxy group) propoxyl group) phenyl) third Acid：White solid；m.p.:125-126℃；1H NMR(300MHz,DMSO-d6)δ:2.12-2.16(m,2H,-CH2-),2.45- 2.47(m,2H,CH2), 2.74 (t, 2H, J=7.5Hz, CH2),4.02-4.13(m,4H,2-OCH2),5.04(s,2H, PhCH2), 5.09 (d, 1H, J=7.8Hz, * CH), 6.85 (d, 2H, J=8.1Hz, Ar-H), 6.93 (d, 2H, J=8.1Hz, ), Ar-H 7.12 (d, 2H, J=8.1Hz, Ar-H), 7.30-7.35 (m, 7H, Ar-H), 8.06 (d, 1H, J=7.8Hz, CONH), 12.40(s,2H,COOH)；13C NMR(75MHz,DMSO-d6)δ:28.6,29.5,35.6,57.4,64.1,64.3,65.6, 114.3,114.3,127.8,127.8,128.4,129.0,129.2,132.9,136.9,155.8,156.8,158.2, 172.4,173.9；HRMS:C28H29NO8[M+Na]+Calculated value 530.1785, measured value 530.1792.
TM3-7 (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (4- propionyl phenoxy group) propoxyl group) phenyl) acetic acid：In vain Color solid；m.p.:93-95℃；1H NMR(300MHz,DMSO-d6)δ:1.06 (t, 3H, J=7.2Hz, CH3),2.16-2.20 (m,2H,-CH2-), 2.97 (q, 2H, J=7.2Hz, 12.3Hz, COCH2),4.13-4.23(m,4H,2-OCH2),5.04(s, 2H,PhCH2), 5.09 (d, 1H, J=8.1Hz, * CH), 6.93 (d, 2H, J=8.4Hz, Ar-H), 7.05 (d, 2H, J= 8.7Hz, Ar-H), 7.30-7.35 (m, 7H, Ar-H), 7.93 (d, 2H, J=8.7Hz, Ar-H), 8.05 (d, 1H, J=8.1Hz, CONH),12.76(s,1H,COOH)；13C NMR(75MHz,DMSO-d6)δ:8.3,28.5,30.8,57.4,64.1,64.6, 65.6,114.3,114.4,127.7,127.8,128.4,129.0,130.1,137.0,155.8,158.1,162.2,172.4, 198.8；HRMS:C28H29NO7[M+H]+Calculated value 492.2017, measured value 492.2021.
TM3-8 (R) -2- (4- (3- (4- acetylbenzenes epoxide) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) amino) acetic acid： White solid；m.p.:120-122℃；1H NMR(300MHz,DMSO-d6)δ:2.16-2.20(m,2H,-CH2-),2.50(s, 3H,COCH3),4.12-4.23(m,4H,2-OCH2),5.03(s,2H,PhCH2), 5.08 (d, 1H, J=8.1Hz, * CH), 6.92 (d, 2H, J=8.4Hz, Ar-H), 7.05 (d, 2H, J=8.4Hz, Ar-H), 7.29-7.34 (m, 6H, Ar-H), 7.92 (d, 2H, J=8.7Hz, Ar-H), 8.05 (d, 1H, J=8.1Hz, CONH), 12.76 (s, 1H, COOH)；13C NMR(75MHz,DMSO- d6)δ:26.4,28.4,57.5,64.1,64.6,65.6,114.3,114.4,127.8,127.9,128.4,129.1,130.5, 136.9,155.9,158.2,162.4,172.4,196.4.
TM3-9 (R) -2- (4- (3- (2- acetylbenzenes epoxide) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) amino) acetic acid： Yellow oil；1H NMR(300MHz,DMSO-d6)δ:2.20-2.28(m,2H,-CH2-),2.55(s,3H,COCH3), 4.14-4.27(m,4H,2-OCH2),5.04(s,2H,PhCH2), 5.09 (d, 1H, J=7.8Hz, * CH), 6.94 (d, 2H, J= 8.7Hz, Ar-H), 7.02 (t, 1H, J=7.5Hz, Ar-H), 7.18 (d, 1H, J=8.1Hz, Ar-H), 7.30-7.60 (m, 9H, ), Ar-H 8.06 (d, 1H, J=8.1Hz, CONH)；13C NMR(75MHz,DMSO-d6)δ:28.6,31.8,57.5,64.5, 65.2,65.6,113.1,114.3,120.4,127.7,127.8,128.4,129.1,129.6,133.9,136.9,155.8, 157.8,158.2,172.4,198.8；HRMS:C27H27NO7[M+H]+Calculated value 478.1860, measured value 478.1864.
TM3-10 (R) -2- (4- (3- (3- acetylbenzenes epoxide) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) amino) second Acid：White solid；m.p.:115-116℃；1H NMR(300MHz,DMSO-d6)δ:2.16-2.20(m,2H,-CH2-),2.56 (s,3H,COCH3),4.13-4.21(m,4H,2-OCH2),5.04(s,2H,PhCH2), 5.09 (d, 1H, J=7.8Hz, * CH), 6.94 (d, 2H, J=8.4Hz, Ar-H), 7.25-7.53 (m, 11H, Ar-H), 8.05 (d, 1H, J=7.8Hz, CONH), 12.75 (s,1H,COOH)；13C NMR(75MHz,DMSO-d6)δ:26.9,28.5,57.0,57.5,64.2,64.4,65.6,113.3, 114.4,119.6,120.8,127.8,128.4,129.0,129.9,138.2,158.2,158.6,172.4,197.8；HRMS: C27H27NO7[M+Na]+Calculated value 500.1680, measured value 500.1685.
TM3-11 (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (5- formoxyl -2- methoxyphenoxies) propoxyl group) Phenyl) acetic acid：White solid；m.p.:106-107℃；1H NMR(300MHz,DMSO-d6)δ:2.17-2.21(m,2H,- CH2-),3.86(s,3H,OCH3),4.13-4.19(m,4H,2-OCH2),5.04(s,2H,PhCH2), 5.09 (d, 1H, J= 7.8Hz, * CH), 6.94 (d, 2H, J=8.4Hz, Ar-H), 7.18 (d, 1H, J=8.1Hz, Ar-H), 7.30-7.35 (m, 7H, ), Ar-H 7.43 (s, 1H, Ar-H), 7.56 (d, 1H, J=8.1Hz, Ar-H), 8.05 (d, 1H, J=8.1Hz, CONH), 9.83 (s,1H,CHO),12.77(s,1H,COOH)；13C NMR(75MHz,DMSO-d6)δ:28.5,55.9,57.5,64.2,65.0, 65.6,110.8,111.5,114.3,126.1,127.8,127.9,128.4,129.0,129.6,136.9,148.3,154.4, 155.8,158.2,172.4,191.4；HRMS:C27H27NO8[M+Na]+Calculated value 516.1629, measured value 516.1632.
TM3-12 (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (4- formoxyl -2- methoxyphenoxies) propoxyl group) Phenyl) acetic acid：White solid；m.p.:191-193℃；1H NMR(300MHz,DMSO-d6)δ:2.17-2.21(m,2H,- CH2-),3.87(s,3H,OCH3),4.11-4.21(m,4H,2-OCH2),5.02(d,3H,PhCH2,*CH),6.92(d,2H,J =7.5Hz, Ar-H), 7.19 (d, 1H, J=8.4Hz, Ar-H), 7.29-7.44 (m, 8H, Ar-H), 7.57 (d, 1H, J= 8.1Hz, Ar-H), 7.91 (d, 1H, J=7.2Hz, CONH), 9.84 (s, 1H, CHO)；13C NMR(75MHz,DMSO-d6)δ: 28.5,55.9,57.5,64.2,65.0,65.5,110.8,111.5,114.3,126.1,127.7,127.8,128.4, 129.0,129.6,137.0,148.3,154.4,155.8,158.1,172.4,191.4；HRMS:C27H27NO8[M+Na]+Calculate Value 516.1629, measured value 516.1632.
TM3-13 (R) -2- (4- (3- (4- acetylaminos phenoxy group) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) amino) second Acid：White solid；m.p.:144-145℃；1H NMR(300MHz,DMSO-d6)δ:1.99(s,3H,COCH3),2.11-2.15 (m,2H,-CH2-),4.07-4.10(m,4H,2-OCH2),5.04(s,3H,PhCH2, * CH), 6.90 (q, 4H, J=9.0Hz, 10.8Hz, Ar-H), 7.29-7.35 (m, 9H, Ar-H), 7.97 (d, 1H, J=7.5Hz, CONH), 9.78 (s, 1H, COOH)；13C NMR(75MHz,DMSO-d6)δ:23.8,28.6,57.5,64.3,65.5,114.3,114.4,120.5,127.7,127.8, 128.4,129.0,129.1,132.6,137.0,154.2,155.8,158.2,167.8,172.4；HRMS:C27H28N2O7[M+ Na]+Calculated value:515.1789, measured value 515.1794.
TM3-14 (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- Phenoxypropoxies) phenyl) acetic acid：White solid； m.p.:73-74℃；1H NMR(300MHz,DMSO-d6)δ:2.13-2.20(m,2H,-CH2-),4.06-4.12(m,4H,2- OCH2),5.04(s,2H,PhCH2), 5.08 (d, 1H, J=7.5Hz, * CH), 6.94-6.95 (m, 4H, Ar-H), 7.25-7.35 (m, 6H, Ar-H), 8.05 (d, 1H, J=7.5Hz, CONH), 12.76 (s, 1H, COOH)；13C NMR(75MHz,DMSO-d6)δ: 28.63,57.45,64.03,64.29,65.56,114.37,114.45,120.58,127.8,128.4,129.0,129.5, 137.0,155.8,158.2,158.5,172.4；HRMS:C25H25NO6[M+Na]+Calculated value 458.1574, measured value 458.1579.
TM3-15 (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- (naphthalene -2- bases epoxide) propoxyl group) phenyl) acetic acid：In vain Color solid；m.p.:94-96℃；1H NMR(300MHz,DMSO-d6)δ:2.22-2.26(m,2H,-CH2-),4.17-4.27(m, 4H,2-OCH2),5.04(s,2H,PhCH2), 5.09 (d, 1H, J=8.1Hz, * CH), 6.95 (d, 2H, J=8.1Hz, Ar-H), 7.18 (d, 1H, J=8.7Hz, Ar-H), 7.31-7.83 (m, 13H, Ar-H), 8.06 (d, 1H, J=7.5Hz, CONH), 12.75 (s,1H,COOH)；13C NMR(75MHz,DMSO-d6)δ:28.6,57.5,64.3,65.6,106.7,114.4,118.7, 123.6,126.4,126.7,127.5,127.7,127.8,128.4,128.5,129.0,129.1,129.3,134.3, 137.0,155.9,156.4,158.2,172.4；HRMS:C29H27NO6[M+Na]+Calculated value 508.1731, measured value 508.1734.
TM3-16 (R) -2- ((benzyloxycarbonyl group) amino) -2- (4- (3- ((2- oxo -2H- chromene -4- bases) epoxide) third oxygen Base) phenyl) acetic acid：White solid；m.p.:98-99℃；1H NMR(300MHz,DMSO-d6)δ:2.26-2.30(m,2H,- CH2-),4.19-4.37(m,4H,2-OCH2),5.07(t,3H,PhCH2,*CH),5.94(s,1H,COCH-),6.95(d,2H,J =8.4Hz, Ar-H), 7.30-7.38 (m, 9H, Ar-H), 7.66 (t, 1H, J=7.5Hz, Ar-H), 7.85 (d, 2H, J= 7.8Hz, Ar-H), 8.05 (d, 1H, J=8.1Hz, CONH), 12.74 (s, 1H, COOH)；13C NMR(75MHz,DMSO-d6)δ: 28.0,57.5,64.2,65.6,66.4,90.6,114.3,114.4,115.2,115.2,116.4,122.9,124.2, 127.8,127.8,128.3,129.0,129.1,129.2,132.7,136.9,152.8,155.8,158.1,161.7, 164.9,172.4；HRMS:C28H25NO8[M+Na]+Calculated value 526.1472, measured value 526.1476.
TM3-17 (R) -2- (4- (3- (benzo [d] oxazole -2- bases sulfenyl) propoxyl group) phenyl) -2- ((benzyloxycarbonyl group) ammonia Base) acetic acid：Gray solid；m.p.:177-178℃；1H NMR(600MHz,DMSO-d6)δ:2.21-2.26(m,2H,-CH2-), 3.46 (t, 2H, J=7.2Hz, SCH2), 4.09 (t, 2H, J=6.0Hz, OCH2), 4.75 (d, 1H, J=6.6Hz, * CH), 5.00 (q, 2H, J=13.2Hz, 26.4Hz, PhCH2),6.83-6.86(m,2H,Ar-H),7.24-7.35(m,11H,Ar-H, CONH)；13C NMR(75MHz,DMSO-d6)δ:28.7,58.7,65.3,65.8,68.1,110.2,113.9,114.1, 114.5,117.3,118.2,124.2,124.6,127.7,127.8,128.4,137.1,141.3,151.2,155.2, 157.4,164.3,171.9；HRMS:C26H24N2O6S[M-H]-Calculated value 491.1271, measured value 491.1280.
TM3-18 (R) -2- (4- (3- (((1H- benzos [d] imidazoles -2- bases) sulfenyl) propoxyl group) phenyl) -2- ((benzyloxy carbonyls Base) amino) acetic acid：White solid；m.p.:111-112℃；1H NMR(300MHz,DMSO-d6)δ:2.17-2.21(m,2H,- CH2-),3.61-3.63(m,3H,SCH2, NH), 4.10 (t, 2H, J=5.8Hz, OCH2),5.05(s,2H,PhCH2),5.09 (d, 1H, J=7.8Hz, * CH), 6.91 (d, 2H, J=8.4Hz, Ar-H), 7.30-7.63 (m, 11H, Ar-H), 8.05 (d, 1H, J=8.1Hz, CONH)；13C NMR(75MHz,DMSO-d6)δ:28.7,28.9,57.4,65.6,65.7,113.3,114.4, 124.0,127.8,127.8,128.4,129.0,129.2,134.6,136.9,150.2,155.8,158.0,172.4；HRMS: C26H25N3O5S[M+H]+Calculated value 492.1588, measured value 492.1595.
The rush GLP-1 secretion activities test of the compound of the mesh of embodiment 6
GLP-1 is the most strong intestines peptide hormone of the promoting insulin secretion having found.Itself and pancreas islet maturation β cells After GLP-1 acceptors are combined, cyclic adenosine monophosphate can be produced with adenosine acyl cyclase, the latter cooperates with stimulation insulin with glucose Synthesis and secrete, stimulate insulin gene transcription and proinsulin biosynthesis, reduce Glucagon concentrations and to suppress pancreas high Blood sugar element secretion, enhancing cell stimulates insulin-dependent Glycogen synthesis, reduces postprandial blood sugar dense to the sensitiveness of insulin Degree；Can be adjusted with activated protein kinase, phosphatidylinositol3 3 kinase (PI3K), MAPK (MAPK) passage The expression of albumen and induction anti-apoptotic proteins Bcl-2 and Bcl-xL promotes its regeneration to slow down β Apoptosis before apoptosis, promotes Beta Cell of islet breaks up and breeds.Due to good physiologically active with more than, nearly 20 years of the research and development of GLP-1 and its related new drug Carry out the focus of always diabetes B drug research.But GLP-1 can be widely present in human blood circulation kidney, DPP IV (dipeptidyl pepidiase-IV, DPP-4) in the tissue such as intestines and stomach, connective tissue, lymph is rapid Degraded, its Half-life in vivo only about 2 minutes causes external source GLP-1 to be difficult to obtain Clinical practice.Therefore, researcher is main at present The related new drug of GLP-1 is developed in terms of 3：Modified GLP-1 or changed structure and obtained the long-acting activators of GLP-1；Research and development are new The DPP-4 inhibitor of grain husk is improving half-life period of endogenous GLP-1；Seek the GLP-1 receptor agonisms with identical physiologically active Agent.
Compound TM1, TM2 and TM3 of the present invention synthesis test of rush GLP-1 secretion activities has been carried out into.Test job by Open innovation style drug research (the Open Innovation of Lilly pharmacy group (Eli Lilly and Company) Drug Discovery, OIDD) platform completion.Current study show that, some cells can be produced under chemical molecular stimulation GLP-1.OIDD chooses mouse STC-1 cells (mSTC-1) and people NCI-H716 cells (hNCI-H716) research testing molecules and lives Change the ability that cell secretes GLP-1.Wherein, hNCI-H716 cells belong to the L-type endocrine cell in enteron aisle, with endocrine Characteristic, can secrete GLP-1 under aliphatic acid, glucosal related protein (GRP), cholinergic agonist, the stimulation of PKA and PKC activators. MSTC-1 cell deriveds can secrete various enteron aisle hormones, including GLP-1, dependence on the glucose in the endocrine tumors of mouse small intestine Property insulin-releasing polypeptide (GIP), cholecystokinin (CCK) and secretin etc..
Materials and methods
1. reagent and consumptive material
DMEM high glucose mediums, the culture mediums of RPMI 1640 are purchased from Hyclone companies.Hyclone (FBS), 4- ethoxys Piperazine ethanesulfonic acid (HEPES), dual anti-(penicillin, streptomysin) is purchased from Invitrogen companies.GLP-1 (7-37) is purchased from Bachem Company.Bovine serum albumin(BSA) (BSA) is purchased from MP Biomedicals companies.AlphaLISA kits, 384 orifice plate Proxi- Plates plus are purchased from Perkin Elmer companies.DPP-4 inhibitor is purchased from Millipore companies.Tissue Culture Plate is purchased from Greiner companies.
384 involved orifice plates are coated with before inoculating cell using poly-D-lysine in experiment, testing compound It is dissolved in dimethyl sulfoxide (DMSO) (DMSO).
2. cell line and condition of culture
MSTC-1 cell lines are isolated from mouse small intestine endocrine tumors.Using DMEM high glucose mediums, addition 10wt% warps Heat-inactivated hyclone, 10mM HEPES and dual anti-, in 5%CO2, 37 DEG C it is incubated.
HNCI-H716 cell lines are purchased from American Type Culture collection (American Type Culture Collection,ATCC).Using the culture mediums of RPMI 1640,10wt% is through heat-inactivated hyclone, 2mM L- paddy ammonia for addition Acid amides, 10mM HEPES and dual anti-, in 5%CO2, 37 DEG C it is incubated.
3. the GLP-1 secretion experiments based on AlphaLISA
For mSTC-1 cells, by the μ L about 12 of every hole 80,000 cell is inoculated in 384 orifice plates, adhere-wall culture.Then, Attached cell is washed 3 times with the HBSS buffer solutions containing 0.1wt%BSA, removes culture medium and serum.Added per hole cell and contained There are the μ L of HBSS buffer solutions 50 of 0.1wt%BSA, add at the testing compound solution of 100nL various concentrations (2 μM, 20 μM) Reason cell (while being to compare with DMSO treatment groups), 37 DEG C are incubated 2 hours, and cell secretes GLP-1 to training under compound stimulation In foster base.Cell secretion GLP-1 detected using corresponding AlphaLISA kits, the multi-functional plate reading machines of Envision (Perkin Elmer) determines fluorescence intensity.
For hNCI-H716 cells, the culture mediums of RPMI 1640 are replaced by " differentiation " culture medium before experiment, that is, contained 10wt% heat-inactivated fetal bovine serums, 10mM HEPES and dual anti-DMEM high glucose mediums.With containing 0.1wt%BSA and The HBSS buffer solutions of 1wt%DPP-4 inhibitor wash attached cell 2 times, remove culture medium and serum, then with the buffer solution weight Suspension cell, according to the μ L about 10 of every hole 50,000 cell is inoculated in 384 orifice plates, prepares the to be measured of various concentrations (2 μM, 20 μM) Compound solution processes cell (while being to compare with DMSO treatment groups) respectively, and 37 DEG C are incubated 2 hours, thin under compound stimulation Intracrine GLP-1 is in culture medium.Cell secretion GLP-1 detected using corresponding AlphaLISA kits, The multi-functional plate reading machines of Envision (Perkin Elmer) determine fluorescence intensity.
With GLP-1 (7-37) polypeptide as standard, using AlphaLISA kit measurements and standard curve is drawn, to experiment Result carries out quantitative analysis.
4. data processing and statistical analysis
The agonist activity (stimulation, stim) of testing compound is calculated according to equation below, wherein Max with Min is respectively the maximum and minimum detection value of control group, and Signal is test group detected value.
Half effective concentration (the EC of testing compound50) returned using 4 parameter logistic and nonlinear regression analysis Calculated.
Experimental result
The rush GLP-1 secretion activity measurement results of the object of the invention compound TM1, TM2 and TM3 are shown in Table six, tested person In compound it is most have promote GLP-1 secretion activities, wherein 14 relatively exciting percentage of the GLP-1 of compound reach 20% with On, active highest is TM1-2b (test value is 57.1%).Further, to showing rush GLP-1 secretions in two cell lines Activity and in a certain cell line compound of the activity more than 20%, and enter in a certain cell line compound of the activity more than 50% EC is gone50Determine, the results are shown in Table six, individual compound shows relatively low toxicity and preferably promotees GLP-1 secretion activities.
The rush GLP-1 secretion activities and EC of the compound TM1 of table six~TM350Measurement result
Note："-" represents undetermined.
The inhibitory activity of Nav 1.7 test of the compound of the mesh of embodiment 7
Neurogenic pain refers to because nervous system sustains damage or produces pain caused by lesion.It is different from By Acute Pain caused by tissue damage, generally in chronic, can last for days or the several months, and routine anodyne such as opiates Potent narcotic antalgesic and non-steroid anti-inflammatory drug are equal without obvious curative effect to it.Its Pathological Physiology feature is mainly shown as The high response of the pain sensation, such as hyperalgia (hyperalgesia), allodynia (allodynia) and idiopathic pain (spontaneous pain) etc..A kind of hypothesis on neurogenic pain mechanism generally acknowledged at present thinks, peripheral nerve The spontaneous pain that is produced after damage and induce bitterly spontaneous with damaged part or dorsal root ganglion neurons and routinely paradoxical discharge It is closely related.The stimulation that the Inflammatory substances that on the one hand this paradoxical discharge triggers with peripheral nerve injury increase and cause has Close, on the other hand to a greater extent depending on the change of Voltage-gated sodium channels.
Voltage-gated sodium channels (voltage-gated sodium channels, VGSCs) are a kind of 6 cross-films Albumen composition, its basic function unit be α subunits.According to the design feature of α subunits, can be divided into 9 kinds of hypotypes (Nav1.1~ Nav1.9).Wherein Nav1.7 great expressions in Primary Sensory Neuron and sympathetic ganglia neurons, most Nav1.7 distributions In the nociceptive neuron of minor diameter, the transmission of pain signal is participated in.Research shows, Nav1.7 passages and many pain Produce and persistently there is clear and definite relation.For example, it is due to being encoded on No. 2 chromosomes innately to lack pain by (CIP) patient The SCN9A genes of Nav1.7 are undergone mutation, and cause Nav1.7 to lose activity completely；Heredity acromelalgia (IE) patient, its There are 13 mutational sites on SCN9A genes, cause Nav1.7 activity to increase；Paroxysmal acrodynia (PEPD) patient, its SCN9A gene Mutational site be different from IE patient, cause the incomplete inactivation of Nav1.7.Many zooperies show that Nav1.7 is in inflammatory pain In also played an important role.Therefore, Nav1.7 passages turn into the target molecule of important pain research.Researchers think, The active size of Nav1.7 can influence human body to the sensitivity of pain, and the selective depressant of the passage may be used with nearly respectively Plant the treatment of pain.Thus, Nav1.7 ion channels high selectivity inhibitor is the focus of analgesic research and development in recent years.
Compound TM1, TM2 and TM3 of the present invention synthesis test of the inhibitory activity of Nav 1.7 has been carried out into.Test job by The OIDD platforms of Lilly pharmacy group (Eli Lilly and Company) are completed.
Materials and methods
1. reagent and consumptive material
DMEM high glucose mediums are purchased from Hyclone companies；Hyclone (FBS), 4- HEPESs (HEPES), dual anti-(penicillin, streptomysin) is purchased from Invitrogen companies；Tissue Culture Plate is purchased from Greiner companies.
Patch-clamp extracellular fluid：NaCl 140mM,KCl 5mM,CaCl2 2mM,MgCl21.1mM, HEPES 10mM, Portugal Grape sugar 10mM, NaOH adjust pH to 7.4.
Testing compound is dissolved in 0.5% dimethyl sulfoxide (DMSO) (DMSO).
2. cell line and condition of culture
The people source embryonic kidney cells HEK293 of expression people's sodium-ion channel Nav 1.7 or Nav 1.5 is public purchased from Millipore Department.Using DMEM high glucose mediums, addition 10wt% through heat-inactivated hyclone, 10mM HEPES and dual anti-, in 5% CO2, 37 DEG C it is incubated.
3. Patch-clamp experiments of sodium-ion channel Nav 1.7
Compound primary dcreening operation and secondary screening use IonWorks Quattro (IWQ) system for automatic patch-clamp system, according to manipulator Volume, sodium ion electric current is recorded from Perforated patch clamp method.Test is first 2~3 days, and the HEK293 cells that will be cultivated under standard conditions connect Plant into T75 Tissue Culture Flasks, culture medium is replaced by patch-clamp extracellular fluid before test.It is ginseng before being added with testing compound According to setting the sealing-in resistance of wave filter end pulses for 25M Ω, current amplitude are 0.5nA removing undesirable experiment Group.For single concentration tests (SP), 3 μM of testing compound solution treatment cells are added, before and after being added by control compounds Current amplitude changes, inhibitory action of the assessment compound to Nav1.7/Nav1.5 electric currents.For concentration dependent experiment (CRC, I.e. many concentration tests), the testing compound solution of configuration various concentrations (0.014-30 μM) processes cell respectively, if keeping current potential It is -110mV, 6 seconds continued stimuluses is spaced using 5Hz electric pulses, that compound is analyzed and calculated according to end pulses uses dependence Property IC50Value or percent inhibition.
Compound is checked using PatchXpress system for automatic patch-clamp systems.
4. data processing and statistical analysis
It is maximum (Max), 0.5% with 12.5 μM of totokaine (tetracaine) treatment groups for single concentration tests DMSO control groups are minimum value (Min), calculate the relative inhibition (inhibition, inhib) of test group.Computing formula is：
Wherein Signal is test group detected value.
For concentration dependent experiment, using 4 parameter logistic regression analyses (XLFit Model), by curved vertex It is modified to 100% inhibiting rate and allows bottom to float.
Experimental result
The Nav1.7 inhibitory activity measurement results of the object of the invention compound TM1, TM2 and TM3 are shown in Table seven.Tested person chemical combination It is most in thing that there is Nav1.7 inhibitory activity, wherein 29 Nav1.7 of compound suppress percentage and reach more than 20%, 8 relatively The Nav1.7 of individual compound is relative to be suppressed percentage and reaches more than 60%, and active highest is that (test value is TM1-18b 89.4%).IC further is carried out to 8 compounds that the relative suppression percentage of Nav1.7 reaches more than 60%50Test, is as a result shown in Table seven, the Nav1.7/Nav1.5 ratios of some molecules (such as TM1-18a, TM1-18b, TM2-a, TM2-b) are larger, selectivity compared with It is good, the potentiality with further investigation.
The Nav1.7 inhibitory activity and IC of the compound TM1~TM3 of the mesh of table seven50Measurement result
Note："-" represents undetermined.
Finally illustrate, preferred embodiment above is merely illustrative of the technical solution of the present invention and unrestricted, although logical Cross above preferred embodiment to be described in detail the present invention, it is to be understood by those skilled in the art that can be Various changes are made to it in form and in details, without departing from claims of the present invention limited range.

Claims (11)

1.D- D-pHPG derivatives, it is characterised in that：With following structural formula：
R1It is methyl, ethyl, n-propyl or normal-butyl, Y is O, and Ar is 3- Fonnylphenyls, 2- Fonnylphenyls, 4- formoxyl benzene Base, 4- methoxycarbonyl groups phenyl, 4- (2- oxo -2- methoxyl groups) ethylphenyl, 4- (3- oxo -3- methoxyl groups) propyl group phenyl, 4- Propionylphenyl, 4- acetylphenyls, 2- acetylphenyls, 3- acetylphenyls, 5- formoxyl -2- methoxyphenyls, 4- first Acyl group -2- methoxyphenyls, 4- acetylamino phenyls, phenyl, naphthalene -2- bases or 2- oxo -2H- chromene -4- bases；
Or, R1It is methyl, ethyl, n-propyl or normal-butyl, Y is S, and Ar is benzo [d] oxazole -2- bases, 1H- benzos [d] miaow Azoles -2- bases, 5- amino -1,3,4- thiadiazoles -2- bases or 4- hydroxyl -6- aminopyrimidine -2- bases；
Or, R1It is methyl, ethyl, n-propyl or normal-butyl, Y is SO2, Ar is 1H- benzos [d] imidazoles -2- bases；
Or, R1It is hydrogen, Y is O, and Ar is 3- Fonnylphenyls, 2- Fonnylphenyls, 4- Fonnylphenyls, 4- carboxyl phenyls, 4- Carboxymethyl phenyl, 4- carboxyethyl phenyls, 4- propionylphenyls, 4- acetylphenyls, 2- acetylphenyls, 3- acetylphenyls, 5- formoxyl -2- methoxyphenyls, 4- formoxyl -2- methoxyphenyls, 4- acetylamino phenyls, phenyl, naphthalene -2- bases or 2- oxygen Generation -2H- chromene -4- bases；
Or, R1It is hydrogen, Y is S, and Ar is benzo [d] oxazole -2- bases or 1H- benzos [d] imidazoles -2- bases.
2. D-pHPG derivative as claimed in claim 1, it is characterised in that：R1It is methyl, Y is O, and Ar is 3- Fonnylphenyl, 2- Fonnylphenyls, 4- methoxycarbonyl groups phenyl, 4- propionylphenyls, 4- acetylphenyls, 2- acetylbenzenes Base, 3- acetylphenyls, 5- formoxyl -2- methoxyphenyls, 4- formoxyl -2- methoxyphenyls, phenyl or 2- oxos -2H- Chromene -4- bases；
Or, R1It is ethyl, Y is O, and Ar is 2- Fonnylphenyls, 2- acetylphenyls, 3- acetylphenyls or phenyl；
Or, R1It is n-propyl, Y is O, and Ar is 4- acetylphenyls, phenyl or naphthalene -2- bases；
Or, R1It is normal-butyl, Y is O, and Ar is 2- Fonnylphenyls or phenyl；
Or, R1Be methyl or ethyl, Y is S, Ar be benzo [d] oxazole -2- bases, 1H- benzos [d] imidazoles -2- bases or 4- hydroxyls - 6- aminopyrimidine -2- bases；
Or, R1It is n-propyl, Y is S, and Ar is 1H- benzos [d] imidazoles -2- bases, 5- amido-1,3,4-thiadiazoles -2- bases or 4- Hydroxyl -6- aminopyrimidine -2- bases；
Or, R1It is normal-butyl, Y is S, and Ar is 1H- benzos [d] imidazoles -2- bases or 4- hydroxyl -6- aminopyrimidine -2- bases；
Or, R1It is methyl, ethyl or n-propyl, Y is SO2, Ar is 1H- benzos [d] imidazoles -2- bases；
Or, R1It is hydrogen, Y is O, and Ar is 4- acetylamino phenyls, phenyl or naphthalene -2- bases；
Or, R1It is hydrogen, Y is S, and Ar is benzo [d] oxazole -2- bases.
3. D-pHPG derivative as claimed in claim 2, it is characterised in that：R1It is methyl, Y is O, and Ar is 4- Acetylphenyl or 2- acetylphenyls；
Or, R1It is ethyl or normal-butyl, Y is O, and Ar is 2- Fonnylphenyls or phenyl；
Or, R1It is n-propyl, Y is O, and Ar is phenyl or naphthalene -2- bases；
Or, R1It is methyl, Y is S, and Ar is 1H- benzos [d] imidazoles -2- bases or 4- hydroxyl -6- aminopyrimidine -2- bases；
Or, R1It is ethyl, Y is S, and Ar is benzo [d] oxazole -2- bases, 1H- benzos [d] imidazoles -2- bases or 4- hydroxyl -6- amino Pyrimidine -2-base；
Or, R1It is methyl or ethyl, Y is SO2, Ar is 1H- benzos [d] imidazoles -2- bases.
4. the preparation method of D-pHPG derivative described in claim 1, it is characterised in that：Step is as follows：
1) D-pHPG and benzene methoxy carbonyl acyl succinimide Z-OSu are reacted into generation intermediate under base catalysis IM1, IM1 again with alcohol R1OH reacts generation intermediate compound I M2 under thionyl chloride effect；
2) intermediate compound I M2 and 1,3- dibromopropanes are reacted into generation intermediate compound I M3 under base catalysis；
3) intermediate compound I M3 and aromatic compound A are reacted into generation D-pHPG derivative TM1 under base catalysis；
4) it is mCPBA reaction generation D- para hydroxybenzenes by D-pHPG derivative TM1-18 and metachloroperbenzoic acid Glycine derivative TM2；
5) generation D-pHPG is acidified after D-pHPG derivative TM1 is hydrolyzed under base catalysis to derive Thing TM3；
Alcohol R1In OH, intermediate compound I M2 and IM3, R1It is methyl, ethyl, n-propyl or normal-butyl；
In aromatic compound A and D-pHPG derivative TM1, R1It is methyl, ethyl, n-propyl or normal-butyl, Y is O, Ar are 3- Fonnylphenyls, 2- Fonnylphenyls, 4- Fonnylphenyls, 4- methoxycarbonyl groups phenyl, 4- (2- oxo -2- methoxies Base) ethylphenyl, 4- (3- oxo -3- methoxyl groups) propyl group phenyl, 4- propionylphenyls, 4- acetylphenyls, 2- acetylbenzenes Base, 3- acetylphenyls, 5- formoxyl -2- methoxyphenyls, 4- formoxyl -2- methoxyphenyls, 4- acetylamino phenyls, benzene Base, naphthalene -2- bases or 2- oxo -2H- chromene -4- bases；Or, R1It is methyl, ethyl, n-propyl or normal-butyl, Y is S, and Ar is benzene And [d] oxazole -2- bases, 1H- benzos [d] imidazoles -2- bases, 5- amino -1,3,4- thiadiazoles -2- bases or 4- hydroxyl -6- amino are phonetic Pyridine -2- bases；
In D-pHPG derivative TM2, R1It is methyl, ethyl, n-propyl or normal-butyl；
In D-pHPG derivative TM3, R1It is hydrogen, Y is O, and Ar is 3- Fonnylphenyls, 2- Fonnylphenyls, 4- first Aminosulfonylphenyl, 4- carboxyl phenyls, 4- carboxymethyls phenyl, 4- carboxyethyl phenyls, 4- propionylphenyls, 4- acetylphenyls, 2- second Aminosulfonylphenyl, 3- acetylphenyls, 5- formoxyl -2- methoxyphenyls, 4- formoxyl -2- methoxyphenyls, 4- acetylaminos Phenyl, phenyl, naphthalene -2- bases or 2- oxo -2H- chromene -4- bases；Or, R1It is hydrogen, Y is S, and Ar is benzo [d] oxazole -2- bases Or 1H- benzos [d] imidazoles -2- bases.
5. the preparation method of D-pHPG derivative as claimed in claim 4, it is characterised in that：Step 1) be by D-pHPG and benzene methoxy carbonyl acyl succinimide Z-OSu are in boiling mixed solvent, potassium carbonate is catalyzed, 15- 35 DEG C, react under the conditions of pH8-9 generation intermediate compound I M1, IM1 again with alcohol R1OH is in heating response generation under thionyl chloride effect Mesosome IM2；
Step 2) be by intermediate compound I M2 and 1,3- dibromopropanes in acetonitrile, potassium carbonate catalysis, react life under the conditions of 45-55 DEG C Into intermediate compound I M3；
Step 3) be by intermediate compound I M3 and aromatic compound A in N,N-dimethylformamide, potassium carbonate catalysis, 15-35 DEG C of bar Generation D-pHPG derivative TM1 is reacted under part；
Step 4) it is anti-by D-pHPG derivative TM1-18 and mCPBA in dichloromethane, under the conditions of 15-35 DEG C D-pHPG derivative TM2 should be generated；
Step 5) be by D-pHPG derivative TM1 in tetrahydrofuran, lithium hydroxide catalysis, 15-35 DEG C of condition After lower hydrolysis generation D-pHPG derivative TM3 is acidified with hydrochloric acid.
Application of the 6.D- D-pHPG derivatives in agent for promoting glucagon-like peptide 1 secretion is prepared, described D- pairs Hydroxyphenylglycine derivative has following structural formula：
R1It is methyl, Y is O, and Ar is 3- Fonnylphenyls, 2- Fonnylphenyls, 2- acetylphenyls, 4- formoxyl -2- methoxyl groups Phenyl, 4- acetylamino phenyls, phenyl or 2- oxo -2H- chromene -4- bases；
Or, R1It is ethyl, Y is O, and Ar is 3- Fonnylphenyls, 2- Fonnylphenyls, 4- Fonnylphenyls, 4- methoxycarbonyl phenyls Base, 4- (2- oxo -2- methoxyl groups) ethylphenyl, 4- (3- oxo -3- methoxyl groups) propyl group phenyl, 4- acetylphenyls, 2- second Aminosulfonylphenyl, 3- acetylphenyls, 4- acetylamino phenyls, phenyl, naphthalene -2- bases or 2- oxo -2H- chromene -4- bases；
Or, R1Be n-propyl, Y is O, Ar be 3- Fonnylphenyls, 2- Fonnylphenyls, 4- Fonnylphenyls, 4- (3- oxos- 3- methoxyl groups) propyl group phenyl, 4- acetylphenyls, 3- acetylphenyls, 5- formoxyl -2- methoxyphenyls, 4- formoxyls -2- Methoxyphenyl, phenyl, naphthalene -2- bases or 2- oxo -2H- chromene -4- bases；
Or, R1It is normal-butyl, Y is O, and Ar is 2- Fonnylphenyls, 4- Fonnylphenyls, 4- (3- oxo -3- methoxyl groups) propyl group Phenyl, 2- acetylphenyls, 5- formoxyl -2- methoxyphenyls, 4- formoxyl -2- methoxyphenyls, 4- acetylamino phenyls, Phenyl or 2- oxo -2H- chromene -4- bases；
Or, R1It is methyl, Y is S, and Ar is benzo [d] oxazole -2- bases；
Or, R1It is ethyl or n-propyl, Y is S, and Ar is benzo [d] oxazole -2- bases or 1H- benzos [d] imidazoles -2- bases；
Or, R1It is methyl, n-propyl or normal-butyl, Y is SO2, Ar is 1H- benzos [d] imidazoles -2- bases；
Or, R1It is hydrogen, Y is O, and Ar is 3- Fonnylphenyls, 2- Fonnylphenyls, 4- Fonnylphenyls, 4- carboxyl phenyls, 4- Carboxymethyl phenyl, 4- propionylphenyls, 4- acetylphenyls, 2- acetylphenyls, 3- acetylphenyls, 5- formoxyl -2- first Phenyl, 4- acetylamino phenyls, phenyl, naphthalene -2- bases or 2- oxo -2H- chromene -4- bases；
Or, R1It is hydrogen, Y is S, and Ar is benzo [d] oxazole -2- bases or 1H- benzos [d] imidazoles -2- bases.
7. D-pHPG derivative as claimed in claim 6 is preparing agent for promoting glucagon-like peptide 1 secretion In application, it is characterised in that in the structural formula of the D-pHPG derivative,
R1It is methyl, Y is O, and Ar is 2- acetylphenyls, phenyl or 2- oxo -2H- chromene -4- bases；
Or, R1It is ethyl or normal-butyl, Y is O, and Ar is 2- Fonnylphenyls or phenyl；
Or, R1It is n-propyl, Y is O, and Ar is phenyl or naphthalene -2- bases；
Or, R1It is ethyl, Y is S, and Ar is benzo [d] oxazole -2- bases；
Or, R1It is n-propyl, Y is SO2, Ar is 1H- benzos [d] imidazoles -2- bases；
Or, R1It is hydrogen, Y is O, and Ar is phenyl or naphthalene -2- bases；
Or, R1It is hydrogen, Y is S, and Ar is benzo [d] oxazole -2- bases.
8. D-pHPG derivative as claimed in claim 7 is preparing agent for promoting glucagon-like peptide 1 secretion In application, it is characterised in that in the structural formula of the D-pHPG derivative,
R1It is ethyl or normal-butyl, Y is O, and Ar is 2- Fonnylphenyls or phenyl；
Or, R1It is n-propyl, Y is O, and Ar is phenyl or naphthalene -2- bases；
Or, R1It is ethyl, Y is S, and Ar is benzo [d] oxazole -2- bases.
Application of the 9.D- D-pHPGs derivative in Voltage-gated sodium channels Nav1.7 inhibitor is prepared, it is described D-pHPG derivative has following structural formula：
R1It is methyl, Y is O, and Ar is 3- Fonnylphenyls, 2- Fonnylphenyls, 4- Fonnylphenyls, 4- methoxycarbonyl groups phenyl, 4- (2- oxo -2- methoxyl groups) ethylphenyl, 4- (3- oxo -3- methoxyl groups) propyl group phenyl, 4- propionylphenyls, 4- acetylbenzenes Base, 2- acetylphenyls, 3- acetylphenyls, 5- formoxyl -2- methoxyphenyls, 4- formoxyl -2- methoxyphenyls, benzene Base, naphthalene -2- bases or 2- oxo -2H- chromene -4- bases；
Or, R1It is ethyl, Y is O, and Ar is 3- Fonnylphenyls, 4- acetylphenyls, 2- acetylphenyls, 3- acetylphenyls Or phenyl；
Or, R1Be n-propyl, Y is O, Ar be 2- Fonnylphenyls, 4- acetylphenyls, 2- acetylphenyls, 5- formoxyls- 2- methoxyphenyls, 4- formoxyl -2- methoxyphenyls, 4- acetylamino phenyls or 2- oxo -2H- chromene -4- bases；
Or, R1It is normal-butyl, Y is O, and Ar is 2- Fonnylphenyls, 4- Fonnylphenyls, 4- methoxycarbonyl groups phenyl, 4- propionos Phenyl, 2- acetylphenyls, 3- acetylphenyls, 4- acetylamino phenyls, naphthalene -2- bases or 2- oxo -2H- chromene -4- bases；
Or, R1It is methyl, ethyl, n-propyl or normal-butyl, Y is S, and Ar is benzo [d] oxazole -2- bases, 1H- benzos [d] miaow Azoles -2- bases, 5- amino -1,3,4- thiadiazoles -2- bases or 4- hydroxyl -6- aminopyrimidine -2- bases；
Or, R1It is methyl, ethyl, n-propyl or normal-butyl, Y is SO2, Ar is 1H- benzos [d] imidazoles -2- bases；
Or, R1Be hydrogen, Y is O, Ar be 4- carboxymethyls phenyl, 4- carboxyethyl phenyls, 4- acetylphenyls, 2- acetylphenyls, 4- formoxyl -2- methoxyphenyls, 4- acetylamino phenyls or naphthalene -2- bases；
Or, R1It is hydrogen, Y is S, and Ar is benzo [d] oxazole -2- bases or 1H- benzos [d] imidazoles -2- bases.
10. D-pHPG derivative as claimed in claim 9 is preparing Voltage-gated sodium channels Nav1.7 Application in inhibitor, it is characterised in that in the structural formula of the D-pHPG derivative,
R1It is methyl, Y is O, and Ar is 3- Fonnylphenyls, 2- Fonnylphenyls, 4- methoxycarbonyl groups phenyl, 4- propionylphenyls, 4- Acetylphenyl, 2- acetylphenyls, 3- acetylphenyls, 5- formoxyl -2- methoxyphenyls, 4- formoxyl -2- methoxyl groups Phenyl, phenyl or 2- oxo -2H- chromene -4- bases；
Or, R1It is ethyl, Y is O, and Ar is 2- acetylphenyls, 3- acetylphenyls or phenyl；
Or, R1It is n-propyl, Y is O, and Ar is 4- acetylphenyls；
Or, R1It is methyl, Y is S, and Ar is benzo [d] oxazole -2- bases, 1H- benzos [d] imidazoles -2- bases or 4- hydroxyl -6- amino Pyrimidine -2-base；
Or, R1It is ethyl or normal-butyl, Y is S, and Ar is 1H- benzos [d] imidazoles -2- bases or 4- hydroxyl -6- aminopyrimidines -2- Base；
Or, R1It is n-propyl, Y is S, and Ar is 1H- benzos [d] imidazoles -2- bases, 5- amido-1,3,4-thiadiazoles -2- bases or 4- Hydroxyl -6- aminopyrimidine -2- bases；
Or, R1It is methyl, ethyl or n-propyl, Y is SO2, Ar is 1H- benzos [d] imidazoles -2- bases；
Or, R1It is hydrogen, Y is O, and Ar is 4- acetylamino phenyls.
11. D-pHPG derivatives as claimed in claim 10 are preparing Voltage-gated sodium channels Nav1.7 Application in inhibitor, it is characterised in that in the structural formula of the D-pHPG derivative,
R1It is methyl, Y is O, and Ar is 4- acetylphenyls or 2- acetylphenyls；
Or, R1It is methyl or ethyl, Y is S, and Ar is 1H- benzos [d] imidazoles -2- bases or 4- hydroxyl -6- aminopyrimidine -2- bases；
Or, R1It is methyl or ethyl, Y is SO2, Ar is 1H- benzos [d] imidazoles -2- bases.
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