CN107151254A - It is a kind of to be used as boric acid compound of 20S proteasome inhibitors and preparation method thereof - Google Patents
It is a kind of to be used as boric acid compound of 20S proteasome inhibitors and preparation method thereof Download PDFInfo
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- CN107151254A CN107151254A CN201610125662.0A CN201610125662A CN107151254A CN 107151254 A CN107151254 A CN 107151254A CN 201610125662 A CN201610125662 A CN 201610125662A CN 107151254 A CN107151254 A CN 107151254A
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- 0 CC(C)CC(*C(C(*)CC1=CCCC=C1)=*)S(O)O Chemical compound CC(C)CC(*C(C(*)CC1=CCCC=C1)=*)S(O)O 0.000 description 10
- JKCINMSCNICCPD-XEAZBWPWSA-N CC(C)C[C@@H](B(O)O[C@@H](C)CC(C1)NC1I)Cl Chemical compound CC(C)C[C@@H](B(O)O[C@@H](C)CC(C1)NC1I)Cl JKCINMSCNICCPD-XEAZBWPWSA-N 0.000 description 1
- DKFIVUREKBDJBZ-VOFUFXJISA-N CCC(C1)([C@@H]2O)NC1C[C@]2(C)O Chemical compound CCC(C1)([C@@H]2O)NC1C[C@]2(C)O DKFIVUREKBDJBZ-VOFUFXJISA-N 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07F—ACYCLIC, CARBOCYCLIC OR HETEROCYCLIC COMPOUNDS CONTAINING ELEMENTS OTHER THAN CARBON, HYDROGEN, HALOGEN, OXYGEN, NITROGEN, SULFUR, SELENIUM OR TELLURIUM
- C07F5/00—Compounds containing elements of Groups 3 or 13 of the Periodic System
- C07F5/02—Boron compounds
- C07F5/025—Boronic and borinic acid compounds
Abstract
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field.Specifically related to new boric acid compound and its production and use, it is especially a kind of to be used as boric acid compound of 20S proteasome inhibitors and preparation method thereof.The invention discloses boric acid compound of Formulas I and preparation method thereof, test, as a result show through bioactivity screening, obtained compound has the function of protease inhibition body, be further useful for preparing treatment and the medicine of proteasome relevant disease.
Description
Technical field
The present invention relates to pharmaceutical chemistry and pharmacotherapeutics field.Specifically related to new boric acid compound and its preparation side
Method and purposes, it is especially a kind of to be used as boric acid compound of 20S proteasome inhibitors and preparation method thereof.
Background technology
It is true that research, which reports Ubiquitin-proteasome path (Ubiquitin-Proteasome Pathway, abbreviation UPP),
The main path of protein degradation in nucleus, can regulate and control to participate in the protein level of cell cycle control, remain different thin
The biological homeostasis of born of the same parents' process.Studies have shown that is in most of mammalian cell, and the path can recognize and degrade mistake
The protein of folding；Experimental results demonstrate, the morbidity of cancer, cardiovascular and cerebrovascular disease and nerve degenerative diseases all with ubiquitin-
Proteasome pathway has important contact.
Research is disclosed in Ubiquitin-proteasome path, and the proteinase complex 26S proteasomes of multi-catalytic are water
The key component of albumen is solved, is made up of two regulation particle 19S proteasomes and a cylindrical 20S proteasome, 19S eggs
White enzyme body is located at the two ends of 20S proteasomes, is made up of 18 subunits, and control protein substrate enters in 20S proteasome cavitys
Identification, folding and transposition；20S proteasomes constitute 4 stacked rings by 28 subunits, wherein 7 different α subunits (α 1- α
7) two exterior chambers, 7 different central lumens of β subunits (the β 1- β 7) formation with proteolytic active sites are formed；Have
The three protein subunit hydrolysing activities closed in central lumen are studied determination, and it includes：There is the subunits of β 1 glutamy to turn peptide water
Solution is active (PGPH), and beta 2 subunit base has trypsin-like activity (T-L), and beta 5 subunit has chymotrypsinlike activity (CT-L).
Bortezomib is the reversible selective proteasome inhibitor of covalent type, mainly suppresses chymotrypsinlike activity, its
Listed in 2003 by Millennium Pharmaceuticals in the U.S., clinical treatment Huppert's disease is had been used at present.However, clinical data
It has been shown that, bortezomib is for example suffered from diarrhoea, vomitted, Painful peripheral neuropathy becomes and blood is small there are still more toxic side effect
Plate reduces disease etc..So far, the mechanism of these toxic side effects is unclear, in addition, the Clinical practice of bortezomib needs often
All intravenous injections or subcutaneous administrations scheme twice, great inconvenience is brought to patient.Therefore, a kind of poison is developed
The novel protease body inhibitor that side effect is low, administration is flexible, can be oral is of great practical significance.
The content of the invention
It is an object of the invention to overcome the defect of prior art there is provided a kind of structure novelty and with protease inhibition body
The boric acid compound of function.
Another object of the present invention is to provide the preparation method of above-mentioned boric acid compound.
Further object of the present invention is to provide above-mentioned boric acid compound related to proteasome for preparing treatment
Purposes in disease medicament.
Specifically,
The invention provides the boric acid compound of Formulas I structure,
Wherein：
X is O or NH；
R is aryl or heteroaryl；
N is 0 or 1.
In some embodiments of the invention, compound of formula I has following structure：
Wherein：
X is O or NH；
R is aryl or heteroaryl；
N is 0 or 1.
In some embodiments of the invention, compound of formula I has following structure：
Wherein：
X is O or NH；
R is aryl or heteroaryl；
N is 0 or 1.
In some embodiments of the invention, Formulas I-a compounds have following structure：
Wherein：
X is O or NH；
R is aryl or heteroaryl；
N is 0 or 1.
In some embodiments of the invention, Formulas I-a compounds have following structure：
Wherein：
X is O or NH；
R is aryl or heteroaryl；
N is 0 or 1.
In some embodiments of the invention, Formulas I-b compounds have following structure：
Wherein：
X is O or NH；
R is aryl or heteroaryl；
N is 0 or 1.
In some embodiments of the invention, Formulas I-b compounds have following structure：
Wherein：
X is O or NH；
R is aryl or heteroaryl；
N is 0 or 1.
In the present invention,
Term " aryl " is used to represent aromatic carbocyclyl groups, including monocyclic or polycyclic aromatic hydrocarbon；
Term " heteroaryl " is used to represent substituted or unsubstituted aromatic carbocyclyl groups, and its ring structure includes 1-4 miscellaneous originals
Son；It is also used for representing the aromatic carbocyclyl groups with two or more rings；
Dotted line and thick line are used for the chemical constitution for representing one or more Stereocenters, indicate chemical constitution neutral body center
Absolute stereochemistry；
In the present invention, the key described in structure schema not represents preferably stereochemical structure, containing one or more vertical
The chemical constitution at body center includes all possible stereoisomer form and its mixture；
Term " inhibitor ", which is used for expression, can block or reduce enzyme, enzyme system, acceptor or the work of other pharmacological targets
The compound of property.
Term " treatment " is used to represent to include reverse, mitigates or prevent the pathological state of clinical disease and correlation, to improve
Or the situation of stable patient.
Invention further provides the preparation method of described compound：
The compound of the present invention can be prepared by a variety of synthetic methods, the part for preparing the compounds of this invention
Raw material can derive from commercial reagents company, and another part can then use concise conversion method well known in the art to prepare.
Specifically, shown compound of Formula I can be prepared according to following general synthetic routes, wherein compound of Formula I
Substituent has previously described meaning.The exemplary only explanation present invention of the synthetic method, and not it is limited to this
Invention.In the present invention, by following route synthesis type I-a compounds：
Formula III -1 obtains formula III -2, formula III -2 and B (OCH under n-BuLi effects3)3Reaction obtains formula III -3, formula
III-3 and III-4-a obtains formula III -5-a, formula III -5-a through ester exchange reaction and reacted with metal reagent i-BuMgBr, then passes through
Anhydrous ZnCl2Catalysis obtains formula III -6-a, formula III -6-a and LiN (SiMe3)2Reaction obtains formula III -7-a, and formula III -7-a exists
The lower deprotection of HCl effects obtains formula III -8-a, and formula III -8-a obtains formula IV -2-a, formula IV -2-a with formula IV -1 through condensation reaction
Remove the group being connected with B and obtain Formulas I-a；
By following route synthesis type I-b compounds：
Formula III -1 obtains formula III -2, formula III -2 and B (OCH under n-BuLi effects3)3Reaction obtains formula III -3, formula
III-3 and III-4-b obtains formula III -5-b, formula III -5-b through ester exchange reaction and reacted with metal reagent i-BuMgBr, then passes through
Anhydrous ZnCl2Catalysis obtains formula III -6-b, formula III -6-b and LiN (SiMe3)2Reaction obtains formula III -7-b, and formula III -7-b exists
The lower deprotection of HCl effects obtains formula III -8-b, and formula III -8-b obtains formula IV -2-b, formula IV -2-b with formula IV -1 through condensation reaction
Remove the group being connected with B and obtain Formulas I-b.
More specifically, the present invention synthesizes compound of Formula I by following routes：
Wherein, the substituent of compound of Formula I has previously described meaning.
Synthesis type I-a compounds：
1) compound of the structure of formula III -1 obtains organic shown in formula III -2 under the conditions of -110 DEG C with n-BuLi reactions
Lithium intermediate；2) compound of the structure of formula III -2 under the conditions of -110 DEG C with B (OCH3)3Reaction obtains the boric acid shown in III-3
Diformazan ester structure；3) compound of the structure of formula III -3 is carried out at ambient temperature with the chiral pinane diol shown in formula III -4-a
Ester exchange reaction obtains the boric acid ester structure shown in III-5-a；
4) compound of formula III -5-a structures is first reacted under the conditions of -78 DEG C with metal reagent i-BuMgBr, rear again in room
Through anhydrous ZnCl under the conditions of temperature2Catalysis obtains the boric acid ester structure shown in III-6-a；
5) compound of formula III -6-a structures under the conditions of -78 DEG C with LiN (SiMe3)2Reaction is obtained shown in formula III -7-a
Double (trimethyl silicane) protection aminoboronic acid ester structure；
6) compound of formula III -7-a structures is obtained under the conditions of -78 DEG C with HCl effect removing double (trimethyl silicanes) protection
Unshielded aminoboronic acid ester hydrochloride structure shown in formula III -8-a；
7) compound of the compound of formula III -8-a structures and the structure of formula IV -1 is in condensing agent 1- (3- dimethylaminos third
Base) -3- ethyl-carbodiimide hydrochlorides (being abbreviated as EDCHCl) and 1- hydroxy benzo triazoles (being abbreviated as HOBt) be present
Under the conditions of reaction obtain boric acid ester structure shown in formula IV -2-a；
8) compound of formula IV -2-a structures is obtained with 2- methyl-propyls boric acid generation ester exchange reaction at ambient temperature
Target boronic acid compounds shown in Formulas I-a.
Synthesis type I-b compounds：
1) compound of the structure of formula III -1 obtains organic shown in formula III -2 under the conditions of -110 DEG C with n-BuLi reactions
Lithium intermediate；
2) compound of the structure of formula III -2 under the conditions of -110 DEG C with B (OCH3)3Reaction obtains the boric acid two shown in III-3
Methyl esters structure；
3) compound of the structure of formula III -3 carries out ester at ambient temperature with the chiral pinane diol shown in formula III -4-b
Exchange reaction obtains the boric acid ester structure shown in III-5-b；
4) compound of formula III -5-b structures is first reacted under the conditions of -78 DEG C with metal reagent i-BuMgBr, rear again in room
Through anhydrous ZnCl under the conditions of temperature2Catalysis obtains the boric acid ester structure shown in III-6-b；
5) compound of formula III -6-b structures under the conditions of -78 DEG C with LiN (SiMe3)2Reaction is obtained shown in formula III -7-b
Double (trimethyl silicane) protection aminoboronic acid ester structure；
6. the compound of formula III -7-b structures is obtained under the conditions of -78 DEG C with HCl effect removing double (trimethyl silicanes) protection
Unshielded aminoboronic acid ester hydrochloride structure shown in formula III -8-b；
7) compound of the compound of formula III -8-b structures and the structure of formula IV -1 is in condensing agent 1- (3- dimethylaminos third
Base) -3- ethyl-carbodiimide hydrochlorides (being abbreviated as EDCHCl) and 1- hydroxy benzo triazoles (being abbreviated as HOBt) be present
Under the conditions of reaction obtain boric acid ester structure shown in formula IV -2-b；
8) compound of formula IV -2-b structures is obtained with 2- methyl-propyls boric acid generation ester exchange reaction at ambient temperature
Target boronic acid compounds shown in Formulas I-b.
The present invention has carried out pharmaceutical research experiment, as a result shows, obtained compound of Formula I has good albumen
Enzyme body inhibitory activity, part of compounds shows good proteasome inhibition activity under nanomolar range, available for preparing
Proteasome inhibitor, for treating the disease related to proteasome.
Embodiment
The present invention is further illustrated with reference to embodiments, but these embodiments are not intended to limit the model of the present invention
Enclose.
A part of raw material for being used to prepare the compounds of this invention in experimental method of the present invention can be public from commercial reagents
Department, another part can then use concise conversion method well known in the art to prepare；Compound structure passes through nuclear magnetic resonance (NMR)
Determined with LC-MS (LCMS)；NMR, which is determined, uses Varian400MHz NMRs, and measure reagent is CDCl3、CD3OD and
DMSO-d6, TMS is inside designated as, chemical shift (δ) is in units of ppm；LCMS is determined using Agilent Technologies6120
LC-MS instrument；Column chromatography uses pressure preparative chromatograph in YAMAZENAI-580S to carry out product purification.
Embodiment 1：Prepare dichloromethylene lithium (compound III-2)
LiCHCl2
(III-2)
Under nitrogen protective condition, anhydrous methylene chloride (4.6mL, 72mmol) is added into 200mL anhydrous tetrahydro furans,
Temperature is down to -110 DEG C, is added dropwise dropwise after 1.6M n-BuLi hexane solution (38mL, 60mmol), completion of dropping, continues
Stirred 1 hour at a temperature of -110 DEG C；Reaction solution is not purified to be directly used in the next step.
Embodiment 2：Prepare dichloromethylene trimethyl borate (compound III-3)
Under nitrogen protective condition, temperature continues to control at -110 DEG C, and the compound III-2 prepared to embodiment 1 is molten
Trimethylborate (8mL, 72mmol) is added in liquid, continues to stir at a temperature of -110 DEG C 1 hour, then adds 5NHCl solution
12mL, reaction is slowly warmed to room temperature, and reaction solution is transferred in separatory funnel, separates organic phase, aqueous phase using ether extraction (3 ×
10mL), merge organic phase, add anhydrous sodium sulfate drying, dry and filtered after finishing, using Rotary Evaporators except solvent obtains white
Solid 8.7g, yield 92%；Reaction product is not purified to be directly used in the next step.
Embodiment 3：Prepare (+)-australene alkane glycol (compound III-4-a)
Under nitrogen protective condition, Me is added into the 100mL tert-butyl alcohols3NO·2H2O (11g, the 102mmol) aqueous solution,
(+)-australene (15mL, 97mmol), pyridine (7mL) and osmium tetroxide (51mg, 0.2mmol) are sequentially added under stirring, then
Backflow is warming up to, TLC detections display reaction is complete after 24 hours, and room temperature is down in reaction, adds NaHSO3(1.2g, 12mmol) is stirred
Mix 1 hour, reaction solution is transferred in separatory funnel, separate organic phase, aqueous phase is merged organic using ether extraction (3 × 20mL)
Phase, adds anhydrous sodium sulfate drying, dries and is filtered after finishing, solvent, column chromatography for separation (petroleum ether are removed using Rotary Evaporators：
Ethyl acetate=30：1) white solid 15g, yield 91% are obtained.
Embodiment 4：Prepare dichloromethylene boric acid-(+)-australene alkane diol ester (compound III-5-a)
The compound III-3 (10g, 63mmol) of embodiment 2 and the chemical combination of embodiment 3 are added into 150mL anhydrous tetrahydro furans
Thing III-4-a (7.2g, 42mmol), is stirred at room temperature, and TLC detections display reaction is complete after 18 hours, is removed using Rotary Evaporators
Solvent, column chromatography for separation (petroleum ether：Ethyl acetate=10：1) colourless oil liquid 10g, yield 91% are obtained.1H NMR(CDCl3,
400MHz) δ 5.39 (s, 1H), 4.46 (d, 1H, J=8.8Hz), 2.33 (m, 2H), 2.12 (t, 1H, J=5.2Hz), 1.94 (m,
2H), (s, the 3H) of 1.46 (s, 3H), 1.30 (s, 3H), 1.21 (d, 1H, J=11.2Hz), 0.84.
Embodiment 5：Prepare 2- methyl -4- chloro- butyl boron dihydroxide-(+)-australene alkane diol ester (compound III-6-a)
Under nitrogen protective condition, the compound III-5 (10g, 38mmol) of embodiment 4 is added into 100mL absolute ethers,
Temperature is down to -78 DEG C, is added dropwise dropwise after 2M selenium alkynide diethyl ether solution (17mL, 33mmol), completion of dropping, adds dry
Dry ZnCl2Powder, reaction is slowly warmed to room temperature, and TLC detections display reaction is complete after 20 hours, is filtered to remove solid, utilizes
Rotary Evaporators remove solvent, column chromatography for separation (petroleum ether：Ethyl acetate=200：1) colourless oil liquid 7.6g, yield are obtained
81%.1H NMR(CDCl3, 400MHz) δ 4.36 (d, 1H, J=9.1Hz), 3.52 (m, 1H), 2.35 (m, 1H), 2.24 (m,
1H), 2.08 (t, 1H, J=5.4Hz), 1.92 (m, 2H), 1.87 (d, 1H, J=1.6Hz), 1.79 (m, 1H), 1.62 (m, 1H),
1.41 (s, 3H), 1.29 (s, 3H), 1.18 (d, 1H, J=11.0Hz), 0.92 (d, 3H, J=6.6Hz), 0.90 (d, 3H, J=
6.6Hz),0.84(s,3H).。
Embodiment 6：2- methyl -4- Amino-butyls boric acid-(+)-australene alkane glycol ester hydrochloride (compound III-8-a)
Preparation
Under nitrogen protective condition, added into 100mL anhydrous tetrahydro furans embodiment 5 compound III-6-a (4.5g,
16mmol), temperature is down to -78 DEG C, and 1M LiN (SiMe are added dropwise dropwise3)2Tetrahydrofuran solution (24mL, 24mmol), is dripped
Bi Hou, reaction is slowly warmed to room temperature, and TLC detections display reaction is complete after 24 hours, removes solvent using Rotary Evaporators, adds
50mL n-hexane dissolutions, are filtered to remove solid, and filtrate temperature is down to -78 DEG C, add 2M HCl diethyl ether solutions (24mL,
48mmol), reaction is slowly warmed to room temperature, and a large amount of white solids occurs, is filtered and is washed with ether, obtains white solid 3.2g,
Yield 66%.1H NMR(DMSO-d6,400MHz)δ7.84(s,3H),7.41(s,1H),7.29(s,1H),7.16(s,1H),
4.44 (m, 1H), 2.74 (m, 1H), 2.32 (m, 1H), 2.18 (m, 1H), 1.99 (t, 1H, J=5.5Hz), 1.88 (m, 1H),
1.73 (m, 2H), 1.47 (m, 2H), 1.35 (s, 3H), 1.24 (s, 3H), 1.11 (d, 1H, J=10.8Hz), 0.86 (d, 6H, J
=6.5Hz), 0.81 (s, 3H).
Embodiment 7：The preparation of (-)-australene alkane glycol (compound III-4-b)
Under nitrogen protective condition, Me is added into the 100mL tert-butyl alcohols3NO·2H2O (11g, the 102mmol) aqueous solution,
(-)-australene (15mL, 97mmol), pyridine (7mL) and osmium tetroxide (51mg, 0.2mmol) are sequentially added under stirring, then
Backflow is warming up to, TLC detections display reaction is complete after 20 hours, and room temperature is down in reaction, adds NaHSO3(1.2g, 12mmol) is stirred
Mix 1 hour, reaction solution is transferred in separatory funnel, separate organic phase, aqueous phase is merged organic using ether extraction (3 × 20mL)
Phase, adds anhydrous sodium sulfate drying, dries and is filtered after finishing, solvent, column chromatography for separation (petroleum ether are removed using Rotary Evaporators：
Ethyl acetate=30：1) white solid 14g, yield 85% are obtained.
Embodiment 8：The preparation of dichloromethylene boric acid-(-)-australene alkane diol ester (compound III-5-b)
The compound III-3 (10g, 63mmol) of embodiment 2 and the chemical combination of embodiment 7 are added into 150mL anhydrous tetrahydro furans
Thing III-4-b (7.2g, 42mmol), is stirred at room temperature, and TLC detections display reaction is complete after 23 hours, is removed using Rotary Evaporators
Solvent, column chromatography for separation (petroleum ether：Ethyl acetate=10：1) colourless oil liquid 9g, yield 81% are obtained.1H NMR(CDCl3,
400MHz) δ 5.39 (s, 1H), 4.46 (d, 1H, J=8.7Hz), 2.33 (m, 2H), 2.12 (t, 1H, J=5.4Hz), 1.94 (m,
2H), (s, the 3H) of 1.46 (s, 3H), 1.30 (s, 3H), 1.20 (d, 1H, J=11.2Hz), 0.84.
Embodiment 9：The preparation of 2- methyl -4- chloro- butyl boron dihydroxide-(-)-australene alkane diol ester (compound III-6-b)
Under nitrogen protective condition, added into 100mL absolute ethers embodiment 8 compound III-5-b (10g,
38mmol), temperature is down to -78 DEG C, and 2M selenium alkynide diethyl ether solution (17mL, 33mmol), completion of dropping are added dropwise dropwise
Afterwards, dry ZnCl is added2Powder, reaction is slowly warmed to room temperature, and TLC detections display reaction is complete after 22 hours, is filtered to remove
Solid, solvent, column chromatography for separation (petroleum ether are removed using Rotary Evaporators：Ethyl acetate=200：1) colourless oil liquid is obtained
5.8g, yield 62%.1H NMR(CDCl3, 400MHz) and δ 4.36 (d, 1H, J=8.8Hz), 3.52 (m, 1H), 2.35 (m, 1H),
2.24 (m, 1H), 2.08 (t, 1H, J=5.4Hz), 1.91 (s, 2H), 1.87 (s, 1H), 1.79 (m, 1H), 1.61 (m, 1H),
1.41 (s, 3H), 1.29 (s, 3H), 1.18 (d, 1H, J=11.1Hz), 0.92 (d, 3H, J=6.6Hz), 0.90 (d, 3H, J=
6.6Hz),0.84(s,3H).。
Embodiment 10：2- methyl -4- Amino-butyls boric acid-(-)-australene alkane glycol ester hydrochloride (compound III-8-b)
Preparation
Under nitrogen protective condition, added into 100mL anhydrous tetrahydro furans embodiment 9 compound III-6-b (4.5g,
16mmol), temperature is down to -78 DEG C, and 1M LiN (SiMe are added dropwise dropwise3)2Tetrahydrofuran solution (24mL, 24mmol), is dripped
Bi Hou, reaction is slowly warmed to room temperature, and TLC detections display reaction is complete after 18 hours, removes solvent using Rotary Evaporators, adds
50mL n-hexane dissolutions, are filtered to remove solid, and filtrate temperature is down to -78 DEG C, add 2M HCl diethyl ether solutions (24mL,
48mmol), reaction is slowly warmed to room temperature, and a large amount of white solids occurs, is filtered and is washed with ether, obtains white solid 4.1g,
Yield 85%.1H NMR(DMSO-d6,400MHz)δ7.85(s,3H),7.42(s,1H),7.29(s,1H),7.16(s,1H),
4.45 (d, 1H, J=8.3Hz), 2.76 (m, 1H), 2.32 (m, 1H), 2.20 (m, 1H), 2.00 (t, 1H, J=5.3Hz), 1.88
(s, 1H), 1.73 (m, 2H), 1.48 (t, 2H, J=7.3Hz), 1.36 (s, 3H), 1.25 (s, 3H), 1.11 (dd, 1H, J=
5.5Hz, J=10.6Hz), 0.86 (d, 6H, J=4.8Hz), 0.82 (s, 3H).
Embodiment 11：(S) preparation of -2- phenoxy groups -3- phenylpropionic acid methyl esters
Under nitrogen protective condition, (R)-PLA methyl esters is sequentially added into 50mL dry toluenes
(1.1g, 6mmol), phenol (0.38g, 4mmol) and triphenylphosphine (1.6g, 6mmol), temperature are down to 0 DEG C of stirring, are added dropwise dropwise
DIAD (1.2g, 6mmol) anhydrous toluene solution, reaction is slowly warmed to room temperature, and TLC detections display reaction is complete after 24 hours,
Solvent is removed using Rotary Evaporators, 10mL ether and 10mL n-hexanes are added into residue, solid is filtered to remove, utilizes rotation
Evaporimeter removes solvent, column chromatography for separation (petroleum ether：Ethyl acetate=50：1) product 0.58g, yield 57% are obtained.1H NMR
(CDCl3, 400MHz) and δ 7.30 (d, 4H, J=4.4Hz), 7.23 (m, 3H), 6.95 (t, 1H, J=7.4Hz), 6.83 (d, 2H, J
=7.8Hz), 4.81 (m, 1H), 3.72 (s, 3H), 3.25 (m, 2H) .MS (ESI) m/z257.0 [M+H]+,279.0[M+Na]+.
(S) preparation of -2- phenoxy groups -3- phenylpropionic acids
(S) -2- phenoxy group -3- phenylpropionic acid methyl esters (0.35g, 1.4mmol) are added into 5mL tetrahydrofurans, room temperature is stirred
Mix, add 7mL 1M sodium hydroxide solutions, TLC detections display reaction is complete after 6 hours, and solvent is removed using Rotary Evaporators, to
6M HCl solution acidifying is added in residue, is extracted (3 × 5mL) using ether, merges organic phase, anhydrous sodium sulfate is added and does
It is dry, dry and filtered after finishing, using Rotary Evaporators except solvent obtains white solid 0.33g, yield 97%.1H NMR(CDCl3,
400MHz) δ 9.94 (s, 1H), 7.29 (m, 7H), 6.98 (t, 1H, J=7.4Hz), 6.85 (d, 2H, J=8.2Hz), 4.85 (m,
1H),3.29(m,2H).MS(ESI)m/z241.0[M-H]-.
The preparation of ((R) -3- methyl isophthalic acids-((S) -2- phenoxy group -3- phenylpropionyls amido) butyl) boric acid (compound I-1)
Under nitrogen protective condition, added into 5mL anhydrous methylene chlorides (S) -2- phenoxy group -3- phenylpropionic acids (27mg,
0.11mmol), be stirred at room temperature, add HOBt (18mg, 0.13mmol), continue stir 10 minutes after add EDCHCl (25mg,
0.13mmol), then add the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL,
0.22mmol), TLC detections display reaction is complete after 13 hours, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid are molten
Liquid, 5%NaHCO3Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing,
Solvent is removed using Rotary Evaporators, products therefrom is added directly into 5mL methanol, is stirred at room temperature, add 2- methyl-propyl boric acid
(22mg, 0.22mmol) and 5mL n-hexanes, then add 1M HCl solution (0.33mL, 0.33mmol), and TLC is examined after 5 hours
Survey display reaction complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate drying, drying is finished
After filter, using Rotary Evaporators remove solvent, column chromatography for separation (dichloromethane：Methanol=100：1) white solid 17mg, production are obtained
Rate 44%.1H NMR(CD3OD,400MHz)δ7.26(m,7H),6.96(m,3H),5.11(m,1H),3.26(m,2H),2.66
(t, 1H, J=7.3Hz), 1.48 (m, 1H), 1.24 (t, 2H, J=7.1Hz), 0.81 (d, 6H, J=6.6Hz) .MS (ESI) m/
z354.0[M-H]-,368.0[M+CH2-H]-,382.0[M+2CH2-H]-.。
Embodiment 12：(S) preparation of -2- (1- naphthoxys) -3- phenylpropionic acid methyl esters
Under nitrogen protective condition, (R)-PLA methyl esters is sequentially added into 50mL dry toluenes
(1.1g, 6mmol), 1- naphthols (0.58g, 4mmol) and triphenylphosphine (1.6g, 6mmol), temperature are down to 0 DEG C of stirring, drip dropwise
Plus DIAD (1.2g, 6mmol) anhydrous toluene solution, react and be slowly warmed to room temperature, TLC detections display has been reacted after 24 hours
Entirely, solvent is removed using Rotary Evaporators, 10mL ether and 10mL n-hexanes is added into residue, solid is filtered to remove, utilized
Rotary Evaporators remove solvent, column chromatography for separation (petroleum ether：Ethyl acetate=60：1) product 0.56g, yield 46% are obtained.1H NMR
(CDCl3, 400MHz) and δ 8.31 (m, 1H), 7.78 (m, 1H), 7.40 (m, 8H), 7.24 (m, 1H), 6.64 (d, 1H, J=
7.6Hz),5.03(m,1H),3.71(s,3H),3.41(m,2H).MS(ESI)m/z307.0[M+H]+,329.0[M+Na]+.
(S) preparation of -2- (1- naphthoxys) -3- phenylpropionic acids
(S) -2- (1- naphthoxys) -3- phenylpropionic acid methyl esters (0.56g, 1.8mmol), room are added into 5mL tetrahydrofurans
Temperature stirring, adds 9mL 1M sodium hydroxide solutions, and TLC detections display reaction is complete after 6 hours, using Rotary Evaporators except molten
Agent, 6M HCl solution acidifying is added into residue, is extracted (3 × 5mL) using ether, merges organic phase, add anhydrous slufuric acid
Sodium is dried, and is dried and is filtered after finishing, using Rotary Evaporators except solvent obtains white solid 0.52g, yield 99%.1H NMR
(CDCl3, 400MHz) and δ 9.68 (s, 1H), 8.27 (m, 1H), 7.79 (m, 1H), 7.39 (m, 9H), 6.67 (d, 1H, J=
7.7Hz),5.07(m,1H),3.44(m,2H).MS(ESI)m/z291.0[M-H]-.
((R) -3- methyl isophthalic acids-((S) -2- (1- naphthoxys) -3- phenylpropionyls amido) butyl) boric acid (compound I-2)
Prepare
Under nitrogen protective condition, (S) -2- (1- naphthoxys) -3- phenylpropionic acids are added into 5mL anhydrous methylene chlorides
(32mg, 0.11mmol), is stirred at room temperature, and adds HOBt (18mg, 0.13mmol), continues to add EDCHCl after stirring 10 minutes
(25mg, 0.13mmol), then add the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL,
0.22mmol), TLC detections display reaction is complete after 16 hours, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid are molten
Liquid, 5%NaHCO3Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing,
Solvent is removed using Rotary Evaporators, products therefrom is added directly into 5mL methanol, is stirred at room temperature, add 2- methyl-propyl boric acid
(22mg, 0.22mmol) and 5mL n-hexanes, then add 1M HCl solution (0.33mL, 0.33mmol), and TLC is examined after 5 hours
Survey display reaction complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate drying, drying is finished
After filter, using Rotary Evaporators remove solvent, column chromatography for separation (dichloromethane：Methanol=80：1) white solid 15mg, production are obtained
Rate 34%.1H NMR(CD3OD, 400MHz) δ 8.24 (m, 1H), 7.80 (m, 1H), 7.36 (m, 9H), 6.84 (t, 1H, J=
7.9Hz), 5.29 (m, 1H), 3.42 (m, 2H), 2.70 (t, 1H, J=7.1Hz), 1.43 (m, 1H), 1.19 (t, 2H, J=
6.1Hz), 0.78 (d, 6H, J=7.3Hz) .MS (ESI) m/z404.0 [M-H]-,418.0[M+CH2-H]-,432.0[M+2CH2-
H]-.。
Embodiment 13：(S) preparation of -3- phenyl -2- (2- pyrazines epoxide) methyl propionate
Under nitrogen protective condition, (R)-PLA methyl esters is sequentially added into 50mL dry toluenes
(1.1g, 6mmol), 2- HYDROXYPYRAZINEs (0.38g, 4mmol) and triphenylphosphine (1.6g, 6mmol), temperature are down to 0 DEG C of stirring, by
DIAD (1.2g, 6mmol) anhydrous toluene solution is added dropwise in drop, and reaction is slowly warmed to room temperature, TLC detections display reaction after 29 hours
Completely, solvent is removed using Rotary Evaporators, 10mL ether and 10mL n-hexanes is added into residue, solid is filtered to remove, profit
Solvent, column chromatography for separation (petroleum ether are removed with Rotary Evaporators：Ethyl acetate=30：1) product 0.47g, yield 45% are obtained.1H
NMR(CDCl3, 400MHz) δ 8.30 (d, 1H, J=1.1Hz), 8.12 (d, 1H, J=2.8Hz), 7.98 (m, 1H), 7.30 (m,
5H),5.42(m,1H),3.71(s,3H),3.28(m,2H).MS(ESI)m/z259.0[M+H]+,281.0[M+Na]+.
(S) preparation of -3- phenyl -2- (2- pyrazines epoxide) propionic acid
(S) -3- phenyl -2- (2- pyrazines epoxide) methyl propionate (0.47g, 1.8mmol) is added into 5mL tetrahydrofurans,
It is stirred at room temperature, adds 9mL 1M sodium hydroxide solutions, TLC detections display reaction is complete after 5 hours, is removed using Rotary Evaporators
Solvent, 6M HCl solution acidifying is added into residue, is extracted (3 × 5mL) using ether, merges organic phase, add anhydrous sulphur
Sour sodium is dried, and is dried and is filtered after finishing, using Rotary Evaporators except solvent obtains white solid 0.39g, yield 89%.1H NMR
(CDCl3,400MHz)δ8.29(s,1H),8.12(s,1H),8.06(s,1H),7.31(m,5H),5.46(m,1H),3.32(m,
2H).MS(ESI)m/z245.0[M+H]+,266.9[M+Na]+.
((R) -3- methyl isophthalic acids-((S) -3- phenyl -2- (2- pyrazines epoxide) propionamido-) butyl) boric acid (compound I-3)
Preparation
Under nitrogen protective condition, (S) -3- phenyl -2- (2- pyrazines epoxide) propionic acid is added into 5mL anhydrous methylene chlorides
(27mg, 0.11mmol), is stirred at room temperature, and adds HOBt (18mg, 0.13mmol), continues to add EDCHCl after stirring 10 minutes
(25mg, 0.13mmol), then add the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL,
0.22mmol), TLC detections display reaction is complete after 17 hours, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid are molten
Liquid, 5%NaHCO3Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing,
Solvent is removed using Rotary Evaporators, products therefrom is added directly into 5mL methanol, is stirred at room temperature, add 2- methyl-propyl boric acid
(22mg, 0.22mmol) and 5mL n-hexanes, then add 1M HCl solution (0.33mL, 0.33mmol), and TLC is examined after 7 hours
Survey display reaction complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate drying, drying is finished
After filter, using Rotary Evaporators remove solvent, column chromatography for separation (dichloromethane：Methanol=60：1) yellow solid 18mg, production are obtained
Rate 46%.1H NMR(CD3OD, 400MHz) δ 8.30 (s, 1H), 8.17 (t, 1H, J=2.6Hz), 8.10 (m, 1H), 7.26 (m,
5H), 5.72 (m, 1H), 3.34 (d, 2H, J=4.9Hz), 2.65 (t, 1H, J=7.3Hz), 1.51 (m, 1H), 1.24 (t, 2H, J
=7.1Hz), 0.83 (d, 6H, J=6.7Hz) .MS (ESI) m/z356.0 [M-H]-,370.0[M+CH2-H]-,384.0[M+
2CH2-H]-.。
Embodiment 14：(S) preparation of -3- phenyl -2- (phenylamino) propionic acid
Under nitrogen protective condition, (S) -2- amino -3- benzene is sequentially added into the anhydrous DMAs of 10mL
Base propionic acid (125mg, 0.75mmol), bromobenzene (80mg, 0.5mmol), potassium carbonate (140mg, 1mmol) and cuprous iodide (15mg,
0.08mmol), temperature rises to 90 DEG C of stirrings, and TLC detections display reaction is complete after 48 hours, and room temperature is down in reaction, adds 5mL second
Acetoacetic ester and 1mL water, temperature are down to 0 DEG C, adjust PH to 3 using 6M HCl solution, separate organic phase, aqueous phase utilizes ethyl acetate
Extract (3 × 10mL), merge organic phase, add anhydrous sodium sulfate drying, dry and filtered after finishing, using Rotary Evaporators except molten
Agent, column chromatography for separation (petroleum ether：Ethyl acetate=2：1) product 69mg, yield 57% are obtained.1H NMR(CDCl3,400MHz)δ
7.31 (m, 4H), 7.20 (t, 3H, J=6.3Hz), 6.84 (t, 1H, J=7.2Hz), 6.65 (d, 2H, J=5.2Hz), 4.30
(m,1H),3.21(m,2H).MS(ESI)m/z240.0[M-H]-.
The system of ((R) -3- methyl isophthalic acids-((S) -3- phenyl -2- (phenylamino) propionamido-) butyl) boric acid (compound I-4)
It is standby
Under nitrogen protective condition, (S) -3- phenyl -2- (phenylamino) propionic acid is added into 5mL anhydrous methylene chlorides
(27mg, 0.11mmol), is stirred at room temperature, and adds HOBt (18mg, 0.13mmol), continues to add EDCHCl after stirring 10 minutes
(25mg, 0.13mmol), then add the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL,
0.22mmol), TLC detections display reaction is complete after 8 hours, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid are molten
Liquid, 5%NaHCO3Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing,
Solvent is removed using Rotary Evaporators, products therefrom is added directly into 5mL methanol, is stirred at room temperature, add 2- methyl-propyl boric acid
(22mg, 0.22mmol) and 5mL n-hexanes, then add 1M HCl solution (0.33mL, 0.33mmol), and TLC is examined after 5 hours
Survey display reaction complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate drying, drying is finished
After filter, using Rotary Evaporators remove solvent, column chromatography for separation (dichloromethane：Methanol=70：1) white solid 14mg, production are obtained
Rate 36%.1H NMR(CD3OD,400MHz)δ7.28(m,7H),7.00(m,3H),4.43(m,1H),3.22(m,2H),2.69
(t, 1H, J=6.6Hz), 1.24 (m, 1H), 1.04 (t, 2H, J=6.2Hz), 0.73 (d, 6H, J=7.2Hz) .MS (ESI) m/
z353.0[M-H]-,367.0[M+CH2-H]-,380.9[M+2CH2-H]-.。
Embodiment 15：(S) preparation of -2- (1- naphthylaminos) -3- phenylpropionic acids
Under nitrogen protective condition, (S) -2- amino -3- benzene is sequentially added into the anhydrous DMAs of 50mL
Base propionic acid (1.2g, 7.2mmol), 1- bromonaphthalenes (1g, 4.8mmol), potassium carbonate (1.3g, 9.6mmol) and cuprous iodide (0.13g,
0.7mmol), temperature rises to 90 DEG C of stirrings, and TLC detections display reaction is complete after 48 hours, and room temperature is down in reaction, adds 30mL second
Acetoacetic ester and 10mL water, temperature are down to 0 DEG C, adjust PH to 3 using 6M HCl solution, separate organic phase, aqueous phase utilizes ethyl acetate
Extract (3 × 20mL), merge organic phase, add anhydrous sodium sulfate drying, dry and filtered after finishing, using Rotary Evaporators except molten
Agent, column chromatography for separation (petroleum ether：Ethyl acetate=2：1) product 0.7g, yield 50% are obtained.1H NMR(DMSO-d6,400MHz)
δ 12.77 (s, 1H), 8.25 (m, 1H), 7.76 (m, 1H), 7.29 (m, 8H), 6.39 (m, 2H), 4.26 (d, 1H, J=0.7Hz),
3.26(m,2H).MS(ESI)m/z289.8[M-H]-.
((R) -3- methyl isophthalic acids-((S) -2- (1- naphthylaminos) -3- phenylpropionyls amido) butyl) boric acid (compound I-5)
Prepare
Under nitrogen protective condition, (S) -2- (1- naphthylaminos) -3- phenylpropionic acids are added into 5mL anhydrous methylene chlorides
(32mg, 0.11mmol), is stirred at room temperature, and adds HOBt (18mg, 0.13mmol), continues to add EDCHCl after stirring 10 minutes
(25mg, 0.13mmol), then add the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL,
0.22mmol), TLC detections display reaction is complete after 16 hours, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid are molten
Liquid, 5%NaHCO3Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing,
Solvent is removed using Rotary Evaporators, products therefrom is added directly into 5mL methanol, is stirred at room temperature, add 2- methyl-propyl boric acid
(22mg, 0.22mmol) and 5mL n-hexanes, then add 1M HCl solution (0.33mL, 0.33mmol), and TLC is examined after 7 hours
Survey display reaction complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate drying, drying is finished
After filter, using Rotary Evaporators remove solvent, column chromatography for separation (dichloromethane：Methanol=50：1) white solid 12mg, production are obtained
Rate 27%.1H NMR(CD3OD, 400MHz) δ 8.10 (d, 1H, J=7.9Hz), 7.92 (m, 1H), 7.76 (d, 1H, J=
8.1Hz), 7.62 (m, 2H), 7.35 (m, 6H), 7.12 (d, 1H, J=7.2Hz), 4.69 (m, 1H), 3.55 (m, 2H), 2.80
(t, 1H, J=7.9Hz), 1.26 (m, 1H), 0.98 (t, 2H, J=7.2Hz), 0.66 (d, 6H, J=7.4Hz) .MS (ESI) m/
z403.3[M-H]-,417.3[M+CH2-H]-,431.3[M+2CH2-H]-.。
Embodiment 16：(S) preparation of -3- phenyl -2- (2- pyrazines amino) propionic acid
Under nitrogen protective condition, (S) -2- amino -3- benzene is sequentially added into the anhydrous DMAs of 50mL
Base propionic acid (1.6g, 9.5mmol), 2- bromo-pyrazines (1g, 6.3mmol), potassium carbonate (1.7g, 12.6mmol) and cuprous iodide
(0.2g, 0.9mmol), temperature rises to 90 DEG C of stirrings, and TLC detections display reaction is complete after 48 hours, and room temperature is down in reaction, is added
30mL ethyl acetate and 10mL water, temperature are down to 0 DEG C, adjust PH to 3 using 6M HCl solution, separate organic phase, aqueous phase utilizes second
Acetoacetic ester extracts (3 × 20mL), merges organic phase, adds anhydrous sodium sulfate drying, dries and is filtered after finishing, utilizes rotary evaporation
Instrument removes solvent, column chromatography for separation (petroleum ether：Ethyl acetate=1：1) product 0.7g, yield 46% are obtained.1H NMR(DMSO-d6,
400MHz) δ 12.66 (s, 1H), 7.99 (d, 1H, J=1.4Hz), 7.87 (m, 1H), 7.65 (d, 1H, J=2.8Hz), 7.40
(d, 1H, J=8.1Hz), 7.26 (d, 3H, J=4.3Hz), 7.18 (m, 1H), 4.55 (m, 1H), 3.14 (m, 1H), 2.96 (m,
1H).MS(ESI)m/z242.0[M-H]-.
((R) -3- methyl isophthalic acids-((S) -3- phenyl -2- (2- pyrazines amino) propionamido-) butyl) boric acid (compound I-6)
Preparation
Under nitrogen protective condition, (S) -3- phenyl -2- (2- pyrazines amino) propionic acid is added into 5mL anhydrous methylene chlorides
(27mg, 0.11mmol), is stirred at room temperature, and adds HOBt (18mg, 0.13mmol), continues to add EDCHCl after stirring 10 minutes
(25mg, 0.13mmol), then add the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL,
0.22mmol), TLC detections display reaction is complete after 13 hours, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid are molten
Liquid, 5%NaHCO3Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing,
Solvent is removed using Rotary Evaporators, products therefrom is added directly into 5mL methanol, is stirred at room temperature, add 2- methyl-propyl boric acid
(22mg, 0.22mmol) and 5mL n-hexanes, then add 1M HCl solution (0.33mL, 0.33mmol), and TLC is examined after 6 hours
Survey display reaction complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate drying, drying is finished
After filter, using Rotary Evaporators remove solvent, column chromatography for separation (dichloromethane：Methanol=50：1) yellow solid 12mg, production are obtained
Rate 31%.1H NMR(CD3OD, 400MHz) δ 7.99 (s, 1H), 7.54 (d, 2H, J=5.8Hz), 7.08 (m, 5H), 3.98 (m,
1H), 2.99 (d, 2H, J=55.0Hz), 2.19 (t, 1H, J=7.6Hz), 1.73 (m, 1H), 1.62 (t, 2H, J=5.7Hz),
0.94 (d, 6H, J=6.1Hz) .MS (ESI) m/z369.1 [M+CH2-H]-,383.3[M+2CH2-H]-.。
Embodiment 17：(S) preparation of -2- (benzyloxy) -3- phenylpropionic acid methyl esters
(S)-PLA methyl esters is added to 50mL dichloromethane and 50mL n-hexanes in the mixed solvent
(2.1g, 11.5mmol), is stirred at room temperature, and 2,2,2- trichloroacetamide benzyl esters (3.5g, 13.8mmol), completion of dropping are added dropwise dropwise
Afterwards, the trifluoromethanesulfonic acid of catalytic amount is added, TLC detections display reaction is complete after 10 hours, and solvent, post are removed using Rotary Evaporators
Chromatography (petroleum ether：Ethyl acetate=50：1) product 1.3g, yield 42% are obtained.1H NMR(CDCl3,400MHz)δ7.22
(m, 10H), 4.67 (d, 1H, J=11.9Hz), 4.37 (d, 1H, J=11.9Hz), 4.14 (m, 1H), 3.72 (s, 3H), 3.06
(m,2H).MS(ESI)m/z271.2[M+H]+,293.2[M+Na]+.
(S) preparation of -2- (benzyloxy) -3- phenylpropionic acids
(S) -2- (benzyloxy) -3- phenylpropionic acid methyl esters (1.3g, 4.8mmol), room temperature are added into 20mL dioxane
Stirring, adds 24mL 2MHCl solution, and temperature rises to TLC detections display after 70 DEG C, 6 hours and reacts complete, adds saturated common salt
Water, solvent is removed using Rotary Evaporators, and aqueous phase profit is extracted with ethyl acetate (3 × 10mL), is merged organic phase, is utilized unsaturated carbonate
Hydrogen sodium solution extract (3 × 10mL), merge aqueous phase, add 6M HCl solution adjust PH to 1, profit be extracted with ethyl acetate (3 ×
20mL), anhydrous sodium sulfate drying is added, dries and is filtered after finishing, using Rotary Evaporators except solvent obtains product 0.94g, yield
76%.1H NMR(CDCl3, 400MHz) and δ 7.23 (m, 10H), 4.65 (d, 1H, J=11.7Hz), 4.42 (d, 1H, J=
11.7Hz),4.20(m,1H),3.12(m,2H).MS(ESI)m/z255.1[M-H]-.
The system of ((R) -1- ((S) -2- (benzyloxy) -3- phenylpropionyls amido) -3- methyl butyls) boric acid (compound I-7)
It is standby
Under nitrogen protective condition, (S) -2- (benzyloxy) -3- phenylpropionic acids are added into 5mL anhydrous methylene chlorides
(28mg, 0.11mmol), is stirred at room temperature, and adds HOBt (18mg, 0.13mmol), continues to add EDCHCl after stirring 10 minutes
(25mg, 0.13mmol), then add the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL,
0.22mmol), TLC detections display reaction is complete after 14 hours, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid are molten
Liquid, 5%NaHCO3Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing,
Solvent is removed using Rotary Evaporators, products therefrom is added directly into 5mL methanol, is stirred at room temperature, add 2- methyl-propyl boric acid
(22mg, 0.22mmol) and 5mL n-hexanes, then add 1M HCl solution (0.33mL, 0.33mmol), and TLC is examined after 5 hours
Survey display reaction complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate drying, drying is finished
After filter, using Rotary Evaporators remove solvent, column chromatography for separation (dichloromethane：Methanol=80：1) white solid 18mg, production are obtained
Rate 44%.1H NMR(CD3OD, 400MHz) δ 7.24 (m, 10H), 4.57 (m, 1H), 4.45 (m, 1H), 4.32 (d, 1H, J=
1.3Hz), 3.06 (m, 2H), 2.65 (t, 1H, J=7.6Hz), 1.52 (m, 1H), 1.39 (t, 2H, J=7.7Hz), 0.86 (d,
6H, J=5.5Hz) .MS (ESI) m/z368.2 [M-H]-,382.2[M+CH2-H]-,396.2[M+2CH2-H]-.。
Embodiment 18：The preparation of 2,2,2- trichloroacetamides (1- menaphthyls) ester
Into 50mL ether add 1- naphthalenes methanol (1.6g, 10mmol), be stirred at room temperature, add 60% sodium hydride (0.8g,
20mmol), continue after stirring 10 minutes, add Tritox (2.2g, 15mmol), TLC detections display has been reacted after 2 hours
Entirely, solvent, column chromatography for separation (petroleum ether are removed using Rotary Evaporators：Ethyl acetate=100：1) product 2g, yield 66% are obtained.1H NMR(CDCl3, 400MHz) and δ 8.50 (s, 1H), 8.07 (d, 1H, J=8.0Hz), 7.90 (t, 2H, J=7.4Hz), 7.65
(d, 1H, J=6.8Hz), 7.53 (m, 3H), 5.79 (s, 2H)
(S) preparation of -2- (1- naphthalenes methoxyl group) -3- phenylpropionic acid methyl esters
To 50mL dichloromethane and 50mL n-hexanes in the mixed solvent add (S)-PLA methyl esters (1g,
5.5mmol), it is stirred at room temperature, 2,2,2- trichloroacetamides (1- menaphthyls) ester (2g, 6.6mmol), completion of dropping is added dropwise dropwise
Afterwards, the trifluoromethanesulfonic acid of catalytic amount is added, TLC detections display reaction is complete after 12 hours, using Rotary Evaporators except solvent is obtained
Product 0.7g, yield 40%.Reaction product is not purified to be directly used in the next step.
(S) preparation of -2- (1- naphthalenes methoxyl group) -3- phenylpropionic acids
(S) -2- (1- naphthalenes methoxyl group) -3- phenylpropionic acid methyl esters (0.7g, 2.2mmol) are added into 20mL dioxane,
It is stirred at room temperature, adds 26mL 2MHCl solution, temperature rises to TLC detections display reaction after 70 DEG C, 4 hours and completely, adds saturation
Saline solution, solvent is removed using Rotary Evaporators, and aqueous phase profit is extracted with ethyl acetate (3 × 10mL), is merged organic phase, is utilized saturation
Sodium bicarbonate solution extracts (3 × 10mL), merges aqueous phase, and the HCl solution for adding 6M adjusts PH to 1, and profit is extracted with ethyl acetate (3
× 20mL), anhydrous sodium sulfate drying is added, dries and is filtered after finishing, using Rotary Evaporators except solvent obtains product 0.12g, production
Rate 18%.1H NMR(CDCl3, 400MHz) and δ 7.45 (m, 12H), 5.12 (d, 1H, J=11.5Hz), 4.84 (d, 1H, J=
11.5Hz),4.31(m,1H),3.12(m,2H).MS(ESI)m/z305.1[M-H]-.
((R) -3- methyl isophthalic acids-((S) -2- (1- naphthalenes methoxyl group) -3- phenylpropionyls amido) butyl) boric acid (compound I-8)
Preparation
Under nitrogen protective condition, (S) -2- (1- naphthalenes methoxyl group) -3- phenylpropionic acids are added into 5mL anhydrous methylene chlorides
(34mg, 0.11mmol), is stirred at room temperature, and adds HOBt (18mg, 0.13mmol), continues to add EDCHCl after stirring 10 minutes
(25mg, 0.13mmol), then add the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL,
0.22mmol), TLC detections display reaction is complete after 14 hours, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid are molten
Liquid, 5%NaHCO3Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing,
Solvent is removed using Rotary Evaporators, products therefrom is added directly into 5mL methanol, is stirred at room temperature, add 2- methyl-propyl boric acid
(22mg, 0.22mmol) and 5mL n-hexanes, then add 1M HCl solution (0.33mL, 0.33mmol), and TLC is examined after 5 hours
Survey display reaction complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate drying, drying is finished
After filter, using Rotary Evaporators remove solvent, column chromatography for separation (dichloromethane：Methanol=100：1) white solid 13mg, production are obtained
Rate 28%.1H NMR(CD3OD, 400MHz) δ 7.99 (m, 1H), 7.85 (t, 2H, J=8.8Hz), 7.35 (m, 9H), 4.94 (d,
1H, J=9.1Hz), 4.62 (s, 1H), 4.42 (m, 1H), 3.05 (m, 2H), 2.59 (t, 1H, J=5.6Hz), 1.60 (m, 1H),
1.42 (t, 2H, J=7.2Hz), 0.84 (d, 6H, J=6.5Hz) .MS (ESI) m/z418.2 [M-H]-,432.2[M+CH2-H]-,
446.2[M+2CH2-H]-.。
Embodiment 19：The preparation of 2,2,2- trichloroacetamides (2- pyrazines methyl) ester
2- methylols pyrazine (100mg, 0.9mmol) is added into 5mL ether, is stirred at room temperature, 60% sodium hydride is added
(80mg, 2mmol), continues after stirring 10 minutes, adds Tritox (202mg, 1.4mmol), TLC detections display after 2 hours
Reaction is complete, and solvent, column chromatography for separation (petroleum ether are removed using Rotary Evaporators：Ethyl acetate=30：1) product 160mg, production are obtained
Rate 70%.1H NMR(CDCl3,400MHz)δ8.79(s,1H),8.56(m,2H),5.51(s,2H).MS(ESI)m/z255.0[M
+H]+.
(S) preparation of -3- phenyl -2- (2- pyrazines methoxyl group) methyl propionate
(S)-PLA methyl esters is added to 5mL dichloromethane and 5mL n-hexanes in the mixed solvent
(180mg, 1mmol), is stirred at room temperature, and 2,2,2- trichloroacetamides (2- pyrazines methyl) ester (316mg, 1.2mmol) is added dropwise dropwise,
After completion of dropping, the trifluoromethanesulfonic acid of catalytic amount is added, TLC detections display reaction is complete after 12 hours, utilizes Rotary Evaporators
Except solvent obtains product 156mg, yield 57%.Reaction product is not purified to be directly used in the next step.
(S) preparation of -3- phenyl -2- (2- pyrazines methoxyl group) propionic acid
Into 5mL dioxane add (S) -3- phenyl -2- (2- pyrazines methoxyl group) methyl propionate (156mg,
0.57mmol), it is stirred at room temperature, adds 6mL 2MHCl solution, temperature rises to TLC detections display after 70 DEG C, 3 hours and reacted
Entirely, saturated aqueous common salt is added, solvent is removed using Rotary Evaporators, aqueous phase profit is extracted with ethyl acetate (3 × 5mL), is merged organic
Phase, is extracted (3 × 5mL) using saturated sodium bicarbonate solution, merges aqueous phase, and the HCl solution for adding 6M adjusts PH to 1, utilizes acetic acid
Ethyl ester extracts (3 × 5mL), adds anhydrous sodium sulfate drying, dries and is filtered after finishing, using Rotary Evaporators except solvent obtains product
36mg, yield 24%.1H NMR(CDCl3, 400MHz) and δ 8.56 (m, 5H), 7.85 (s, 1H), 7.31 (d, 2H, J=6.0Hz),
(m, the 2H) of 4.85 (s, 1H), 4.25 (d, 1H, J=14.1Hz), 4.07 (d, 1H, J=14.1Hz), 3.24
((R) -3- methyl isophthalic acids-((S) -3- phenyl -2- (2- pyrazines methoxyl group) propionamido-) butyl) boric acid (compound I-
9) preparation
Under nitrogen protective condition, (S) -3- phenyl -2- (2- pyrazines methoxyl group) third is added into 5mL anhydrous methylene chlorides
Sour (28mg, 0.11mmol), is stirred at room temperature, and adds HOBt (18mg, 0.13mmol), continues to add EDC after stirring 10 minutes
HCl (25mg, 0.13mmol), then add the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL,
0.22mmol), TLC detections display reaction is complete after 20 hours, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid are molten
Liquid, 5%NaHCO3Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing,
Solvent is removed using Rotary Evaporators, products therefrom is added directly into 5mL methanol, is stirred at room temperature, add 2- methyl-propyl boric acid
(22mg, 0.22mmol) and 5mL n-hexanes, then add 1M HCl solution (0.33mL, 0.33mmol), and TLC is examined after 7 hours
Survey display reaction complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate drying, drying is finished
After filter, using Rotary Evaporators remove solvent, column chromatography for separation (dichloromethane：Methanol=30：1) yellow solid 12mg, production are obtained
Rate 29%.1H NMR(CD3OD, 400MHz) δ 8.60 (t, 2H, J=34.3Hz), 8.02 (d, 1H, J=7.9Hz), 7.61 (m,
6H), 4.39 (d, 1H, J=13.7Hz), 4.22 (d, 1H, J=14.1Hz), 3.72 (m, 1H), 3.20 (m, 2H), 2.91 (t,
1H, J=12.9Hz), 2.02 (m, 1H), 1.56 (t, 2H, J=7.2Hz), 0.94 (d, 6H, J=24.5Hz) .MS (ESI) m/
z370.1[M-H]-,398.2[M+2CH2-H]-.。
Embodiment 20：(S) preparation of -2- (benzyl amino) -3- phenylpropionic acids
(S) -2- amino -3- phenylpropionic acids (165mg, 1mmol) are added into 10mL water, is stirred at room temperature, sequentially adds benzyl
Chlorine (158mg, 1.3mmol) and potassium carbonate (138mg, 1mmol), add benzyl chloride (158mg, 1.3mmol) and carbonic acid after 1 hour
Potassium (138mg, 1mmol), TLC detections display reaction is complete after 24 hours, filters and is washed with ether, filter cake utilizes 6M HCl
Solution is acidified, and a large amount of white solids is occurred, is filtrated to get product 201mg, yield 79%.1H NMR(D2O-NaOH,400MHz)δ
7.05 (m, 10H), 3.48 (d, 1H, J=12.7Hz), 3.30 (d, 1H, J=12.8Hz), 3.07 (t, 1H, J=6.8Hz),
2.63(m,2H).MS(ESI)m/z254.1[M-H]-.
The system of ((R)-((S) -2- (benzyl amino) -3- phenylpropionyls amido) -3- methyl butyls) boric acid (compound I-10)
It is standby
Under nitrogen protective condition, (S) -2- (benzyl amino) -3- phenylpropionic acids are added into 5mL anhydrous methylene chlorides
(28mg, 0.11mmol), is stirred at room temperature, and adds HOBt (18mg, 0.13mmol), continues to add EDCHCl after stirring 10 minutes
(25mg, 0.13mmol), then add the compound III-8-a (50mg, 0.17mmol) of embodiment 6 and DIPEA (0.04mL,
0.22mmol), TLC detections display reaction is complete after 10 hours, and reaction solution uses 5%NaHCO respectively3Solution, 10% citric acid are molten
Liquid, 5%NaHCO3Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, is dried and is filtered after finishing,
Solvent is removed using Rotary Evaporators, products therefrom is added directly into 5mL methanol, is stirred at room temperature, add 2- methyl-propyl boric acid
(22mg, 0.22mmol) and 5mL n-hexanes, then add 1M HCl solution (0.33mL, 0.33mmol), and TLC is examined after 3 hours
Survey display reaction complete, stand reaction solution to being layered, lower floor is washed with n-hexane, add anhydrous sodium sulfate drying, drying is finished
After filter, using Rotary Evaporators remove solvent, column chromatography for separation (dichloromethane：Methanol=50：1) white solid 11mg, production are obtained
Rate 27%.1H NMR(CD3OD, 400MHz) δ 7.23 (m, 10H), 3.72 (d, 1H, J=13.1Hz), 3.62 (d, 1H, J=
6.8Hz), 3.37 (t, 1H, J=6.9Hz), 3.11 (m, 2H), 2.90 (t, 1H, J=9.9Hz), 2.03 (m, 1H), 1.59 (t,
2H, J=8.2Hz), 0.85 (d, 6H, J=13.5Hz) .MS (ESI) m/z367.1 [M-H]-,395.3[M+2CH2-H]-.。
Embodiment 21：(S) preparation of -2- ((1- menaphthyls) amino) -3- phenylpropionic acids
(S) -2- amino -3- phenylpropionic acids (1g, 6mmol) are added into 50mL water, is stirred at room temperature, sequentially adds 1- chloromethanes
Base naphthalene (1.3g, 7.5mmol) and potassium carbonate (0.9g, 6mmol), add 1 chloromethyl naphthalene (1.3g, 7.5mmol) after 1 hour
With potassium carbonate (0.9g, 6mmol), TLC detections display reaction is complete after 30 hours, filters and is washed with ether, filter cake utilizes 6M
HCl solution acidifying, there are a large amount of white solids, be filtrated to get product 0.69g, yield 38%.1H NMR(CD3OD,400MHz)
δ 7.60 (m, 12H), 4.75 (d, 1H, J=13.2Hz), 4.59 (d, 1H, J=13.7Hz), 4.09 (m, 1H), 3.24 (m, 2H)
.MS(ESI)m/z306.2[M+H]+.
((R) -3- methyl isophthalic acids-((S) -2- ((1- menaphthyls) amino) -3- phenylpropionyls amido) butyl) boric acid (compound
I-11 preparation)
Under nitrogen protective condition, (S) -2- ((1- menaphthyls) amino) -3- phenyl is added into 5mL anhydrous methylene chlorides
Propionic acid (34mg, 0.11mmol), is stirred at room temperature, and adds HOBt (18mg, 0.13mmol), continues to add after stirring 10 minutes
EDCHCl (25mg, 0.13mmol), then adds the compound III-8-a (50mg, 0.17mmol) and DIPEA of embodiment 6
(0.04mL, 0.22mmol), TLC detections display reaction is complete after 15 hours, and reaction solution uses 5%NaHCO respectively3Solution, 10%
Citric acid solution, 5%NaHCO3Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, has been dried
Filtered after finishing, solvent is removed using Rotary Evaporators, products therefrom is added directly into 5mL methanol, is stirred at room temperature, add 2- methyl
Propyl boric acid (22mg, 0.22mmol) and 5mL n-hexanes, then add 1M HCl solution (0.33mL, 0.33mmol), 5 hours
TLC detections display reaction is complete afterwards, stands reaction solution to being layered, lower floor is washed with n-hexane, adds anhydrous sodium sulfate drying, is done
It is dry finish after filter, using Rotary Evaporators remove solvent, column chromatography for separation (dichloromethane：Methanol=50：1) white solid is obtained
13mg, yield 28%.1H NMR(CD3OD,400MHz)δ7.53(m,12H),4.15(m,2H),3.72(m,1H),3.02(d,
2H, J=7.2Hz), 2.61 (t, 1H, J=7.4Hz), 1.48 (m, 1H), 1.08 (t, 2H, J=6.9Hz), 0.83 (d, 6H, J=
7.5Hz).MS(ESI)m/z417.2[M-H]-,431.2[M+CH2-H]-,445.3[M+2CH2-H]-.。
Embodiment 22：(S) preparation of -3- phenyl -2- ((2- pyrazines methyl) amino) propionic acid
(S) -2- amino -3- phenylpropionic acids (83mg, 0.5mmol) are added into 5mL water, is stirred at room temperature, sequentially adds 2-
Chloromethylpyrazine (75mg, 0.6mmol) and potassium carbonate (69mg, 0.5mmol), add 2- chloromethylpyrazines after 1 hour
(75mg, 0.6mmol) and potassium carbonate (69mg, 0.5mmol), TLC detections display reaction is complete after 26 hours, filters and uses ether
Washing, filter cake is acidified using 6M HCl solution, a large amount of faint yellow solids is occurred, is filtrated to get product 103mg, yield 80%.1H
NMR(D2O-NaOH, 400MHz) δ 8.08 (m, 3H), 6.86 (m, 5H), 3.49 (d, 1H, J=14.4Hz), 3.33 (d, 1H, J=
14.6Hz),2.90(m,1H),2.48(m,2H).MS(ESI)m/z256.0[M-H]-.
((R) -3- methyl isophthalic acids-((S) -3- phenyl -2- ((2- pyrazines methyl) amino) propionamido-) butyl) boric acid (chemical combination
Thing I-12) preparation
Under nitrogen protective condition, (S) -3- phenyl -2- ((2- pyrazines methyl) ammonia is added into 5mL anhydrous methylene chlorides
Base) propionic acid (28mg, 0.11mmol), it is stirred at room temperature, adds HOBt (18mg, 0.13mmol), continues to add after stirring 10 minutes
EDCHCl (25mg, 0.13mmol), then adds the compound III-8-a (50mg, 0.17mmol) and DIPEA of embodiment 6
(0.04mL, 0.22mmol), TLC detections display reaction is complete after 17 hours, and reaction solution uses 5%NaHCO respectively3Solution, 10%
Citric acid solution, 5%NaHCO3Solution and saturated common salt water washing, anhydrous sodium sulfate drying is added into organic phase, has been dried
Filtered after finishing, solvent is removed using Rotary Evaporators, products therefrom is added directly into 5mL methanol, is stirred at room temperature, add 2- methyl
Propyl boric acid (22mg, 0.22mmol) and 5mL n-hexanes, then add 1M HCl solution (0.33mL, 0.33mmol), 6 hours
TLC detections display reaction is complete afterwards, stands reaction solution to being layered, lower floor is washed with n-hexane, adds anhydrous sodium sulfate drying, is done
It is dry finish after filter, using Rotary Evaporators remove solvent, column chromatography for separation (dichloromethane：Methanol=50：1) yellow solid is obtained
11mg, yield 27%.1H NMR(CD3OD,400MHz)δ8.09(s,1H),7.21(s,1H),6.95(s,1H),6.13(m,
5H), 4.04 (d, 1H, J=13.4Hz), 3.81 (d, 1H, J=3.2Hz), 3.54 (m, 1H), 3.15 (m, 2H), 2.80 (t, 1H,
), J=8.9Hz 2.02 (m, 1H), 1.58 (t, 2H, J=10.2Hz), 0.89 (d, 6H, J=7.3Hz) .MS (ESI) m/z369.0
[M-H]-,397.0[M+2CH2-H]-.。
Embodiment 23：The determination experiment of the compounds of this invention proteasome inhibition activity
Use and tested purchased from Chemicon (Chemicon, USA) 20S proteasome kits in the present embodiment.
The general principle of the method for testing is 20S proteasomes hydrolysis fluorogenic substrate Suc-LLVY-AMC (Suc-Leu-Leu-Val-
Tyr-AMC, Suc are succinyl group, and AMC is 7- acid amides -4- methylcoumarins), the AMC with fluorescence is discharged, by changing
The concentration of compound to be tested, is measured using SpectraMax M5 ELIASAs (380nm/460nm) and is discharged under various concentrations
AMC fluorescent value, so that judge inhibition level of the compound to 20S proteasome chymotrypsinlike activities site (CT-L), profit
The IC that compound suppresses to 20S proteasome chymotrypsinlike activities site is calculated with GraphPad Prism softwares50Value；Table 1
The IC that part of compounds suppresses to 20S proteasome chymotrypsinlike activities site is now shown50Value is such as.
Inhibitory action of the test-compound of table 1. to mankind's 20S proteasome chymotrypsinlike activities site
·IC50It is worth for the average value of independent experiment at least twice.
Claims (9)
1. the boric acid compound of Formulas I structure,
Wherein：
X is O or NH；
R is aryl or heteroaryl；
N is 0 or 1.
2. boric acid compound according to claim 1, it is characterised in that the compound is the change with following structures
Compound,
3. boric acid compound according to claim 1, it is characterised in that the compound is the change with following structures
Compound,
4. boric acid compound according to claim 2, it is characterised in that the compound is the change with following structures
Compound,
5. boric acid compound according to claim 2, it is characterised in that the compound is the change with following structures
Compound,
6. boric acid compound according to claim 3, it is characterised in that the compound is the change with following structures
Compound,
7. boric acid compound according to claim 3, it is characterised in that the compound is the change with following structures
Compound,
8. purposes of any described compound in proteasome inhibitor is prepared in claim 1-7.
9. the purposes as described in claim 8, described proteasome inhibitor is treatment and the medicine of proteasome relevant disease
Thing.
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Citations (2)
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| US20030199561A1 (en) * | 1994-10-28 | 2003-10-23 | Millennium Pharmaceuticals, Inc. | Boronic ester and acid compounds, synthesis and uses |
| US20150329565A1 (en) * | 2012-12-03 | 2015-11-19 | Hoffmann-La Roche Inc. | Substituted triazole boronic acid compounds |
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2016
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| US20030199561A1 (en) * | 1994-10-28 | 2003-10-23 | Millennium Pharmaceuticals, Inc. | Boronic ester and acid compounds, synthesis and uses |
| CN101077875A (en) * | 1994-10-28 | 2007-11-28 | 千年药物公司 | Boronic ester and acid compounds, synthesis and uses |
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