CN105732683B - The dipeptide boronic acid and its ester type compound, preparation method and its usage of a kind of carboxylic acid and alpha amino acid composition - Google Patents
The dipeptide boronic acid and its ester type compound, preparation method and its usage of a kind of carboxylic acid and alpha amino acid composition Download PDFInfo
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- CN105732683B CN105732683B CN201610186292.1A CN201610186292A CN105732683B CN 105732683 B CN105732683 B CN 105732683B CN 201610186292 A CN201610186292 A CN 201610186292A CN 105732683 B CN105732683 B CN 105732683B
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- 0 CC=C=CC(C)=CN=C* Chemical compound CC=C=CC(C)=CN=C* 0.000 description 5
- FLZVNAUDBQHCMF-VIFPVBQESA-N COC([C@H](Cc1ccc(C(F)(F)F)cc1)N)=O Chemical compound COC([C@H](Cc1ccc(C(F)(F)F)cc1)N)=O FLZVNAUDBQHCMF-VIFPVBQESA-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 invention belongs to pharmaceutical synthesis fields, and in particular to a series of new peptide boric acid and its ester type compound or its pharmaceutical salts, preparation method and the application in pharmacodynamics.The peptide boric acid and its ester type compound of the present invention or its pharmaceutical salts, structure is shown in formula I,
Description
Technical field
The invention belongs to pharmaceutical synthesis fields, and in particular to the preparation side of a series of new peptide boric acid and its ester type compound
Method and its application in pharmacodynamics.
Background technology
Currently, cancer is to endanger one of most important disease of human health.Although the treatment of cancer at present operative treatment,
The fields such as chemotherapy, radiotherapy have been achieved for prodigious progress, but can't fundamentally treating cancer.Although at present
The anticancer drug of listing has certain curative effect, but they have serious toxic side effect.Therefore, further investigated and research how
Become the task of top priority of medical personal from effective tumor targets to study the new anticancer drug of targeting.
Ubiquitin-Proteasome Pathway (Ubiquitin-Proteasome Pathway, abbreviation UPP) is intracellular protein
The main path of system degradation, and many physiologically important cellular processes are participated in, including signal transduction, immune response are not rolled over
Folded albumen reaction and cell cycle progress.This approach and cardiovascular and cerebrovascular disease, the hair of cancer and nervous system degenerative disease
Disease etc. suffers from important relationship.Inhibit the protein that excessive degradation is important in this approach using some effective inhibitor
New thinking will be provided for the treatment of above-mentioned disease.For this novel target spot, first proteasome inhibitor in 2003
Bortezomib (PS-341) obtains FDA approval listings, for treating recurrent myeloma.The medicine goes through in European Union again within 2004
City, and it is used for Huppert's disease.In September, 2005, the medicine are introduced by Xi'an Yang Sen, are listed for the first time in China Guangzhou.2005,
The medicine obtains " PrixGalien " prize of the Nobel Prize title with the world of medicine in France, Holland and Belgium simultaneously.
It is approved by the fda in the United States for treatment relapsed or stubborn lymphoma mantle cell (Mantle Cell again on July 11st, 2007
Lymphoma, abbreviation MCL), become the currently the only drug for obtaining FDA approvals for treating MCL.FDA approval Bortezomibs can carry out
Subcutaneous administration, this not only makes Bortezomib be absorbed as being easy, also greatly improves tolerance of the patient to Bortezomib, reduce secondary work
With.
The sales volume of Bortezomib in 2014, which reaches 30.69 hundred million dollars, becomes one of best-selling tumour medicine top20 in the whole world.Ten thousand
Jade-like stone is every 3.5 milligrams about 10,000 three thousand yuan in Chinese market price, about 40,000 yuan for the treatment of a cycle expense, so expensive expense
It is very heavy financial burden for many patients.Moreover, current clinical data is shown, there is also relatively more for this kind of drug
Side effect, such as tired weak, nauseous, diarrhea and neuropathy.Therefore, a kind of cheap, malicious pair how is developed
It is that we need key problems-solving at present to act on low high therapeutic protein enzyme body inhibitor medicaments.
For the target spot of this curative effect confirmation, we devise a series of completely new boric acid class proteasome of structures and inhibit
Agent.
Invention content
The purpose of the present invention is synthesize a series of structure novels and novel boric acid with proteasome inhibition function and its
Ester type compound.As 20S proteasome inhibitors, they can effectively block tumor cell proliferation, induced tumor cell to wither
It dies, for the prevention and treatment of a variety of diseases of humans and animals such as malignant tumour.
It is a further object of the present invention to provide the preparation methods of a kind of above-mentioned peptide boric acid and its ester type compound.
It is a still further object of the present invention to provide a kind of above-mentioned peptide boric acids and its ester type compound to prepare antitumor drug
The application of aspect.
The purpose of the present invention specifically can be reached by the following measures：
A kind of peptide boric acid and its ester type compound, structure is shown in formula I,
Wherein：
R1Selected from C1~10Alkyl, C1~10Alkoxy, C1~10Alcoxyl C1~10Alkyl, phenyl, naphthalene, tetralyl or heterocycle
Base, or optionally by C1~4Alkyl, C1~4Alkoxy, C1~4Naphthenic base, halogen or halogenated C1~4Alkyl replaces；R1Preferably
C1~10Alkyl, C1~10Alkoxy, C1~10Alkoxyl-methyl, C1~10Alkoxyl oxygen alkyl ethyl, phenyl, pyrazinyl, pyridyl group, naphthalene, naphthane
Base, or optionally by C1~4Alkyl, C1~4Alkoxy, halogen or halogenated C1~4Alkyl replaces.
Further, R1Further preferably：
Wherein R3And R4Independently selected from hydrogen, methyl, methoxyl group, ethyl, ethyoxyl, chlorine, bromine, fluorine or trifluoromethyl.
R2Selected from C1~10Alkyl, C3~6Naphthenic base or Heterocyclylalkyl, phenyl, naphthalene or indyl, or optionally by C1~4
Alkyl, C1~4Alkoxy, cyano, nitro, hydroxyl, sulfydryl, amino or halogen substitution；R2Preferably phenyl, methoxyl group, first sulfydryl,
Cyclohexyl, or optionally by C1~4Alkyl, C1~4Alkoxy, nitro or halogen substitution.
Z1Or Z2Independently selected from hydroxyl, C1~10Alkyl, C1~10Alkoxy or aryloxy group or B, Z1And Z2Together
Form the heterocyclic group containing N, S or O or B and Z1And Z2The group containing O heterocycles is formed together, and is connected with boron atom
Be oxygen atom.Preferably, Z1Or Z2Independently selected from hydroxyl, C1~10Alkyl, C1~10Alkoxy or aryloxy group or B, Z1With
Z2Boric acid-australene alkane diol ester or B and Z are formed together1And Z2Borate is formed together, and what is be connected with boron atom is oxygen
Atom.It is further preferred that Z1Or Z2It is independently selected from hydroxyl or B, Z1And Z2Boric acid-australene alkane diol ester is formed together, or
Person B, Z1And Z2Diethanol amine ester and other prodrugs are formed together.
R of the present invention1、R2" optionally by ... substitution " in group refers to R1、R2Group can be replaced by these groups,
The case where can not also being replaced by these groups, that is, being not limited in being replaced by these cited groups also includes not by institute
The case where these groups substitution enumerated.This expression way and " R1For substituted or non-substituted C1~10Alkyl, C3~6Ring
Alkyl or Heterocyclylalkyl, phenyl, naphthalene or indyl, wherein substituent group are C1~4Alkyl, C1~4Alkoxy, cyano, hydroxyl
The expression way of base, sulfydryl, amino or halogen " is identical, but substituted or non-substituted restriction not only narrowly refers to C1~10's
Alkyl, but be expanded to all groups, that is, include substituted or non-substituted C3~6Naphthenic base or Heterocyclylalkyl, substitution
Or non-substituted benzyl, substituted or non-substituted menaphthyl, substituted or non-substituted indole methyl etc., wherein substituent group is C1~4
Alkyl, C1~4Alkoxy, cyano, hydroxyl, sulfydryl, amino or halogen.
Term " alkyl " is for indicating saturated hydrocarbyl, C1~10Alkyl refer to the saturated hydrocarbyl containing 1~10 carbon atom,
C1~4Alkyl refer to the saturated hydrocarbyl containing 1~4 carbon atom.
Term " naphthenic base " refers to non-aromatic carbocyclyl, includes the alkyl of cyclisation.Naphthenic base may include two rings or polycyclic system
System.The example of naphthenic base includes cyclopropyl, cyclobutyl, cyclopenta, cyclohexyl, suberyl, C3~6Naphthenic base refer to containing 3~6
The naphthenic base of a carbon atom.
Term " benzyl " refers to benzyl, substituted benzyl refer on the phenyl ring of benzyl at least one hydrogen atom by non-hydrogen
Part replaces, and the substituent group of benzyl can be halogen ,-CN ,-OH ,-SH ,-NH2, the linear or branched alkyl group of 1-6 carbon, 1-6
The substituted linear or branched alkyl group of a carbon.
Term " Heterocyclylalkyl " refers to non-aromatic miscellaneous carbocylic radical, includes the alkyl of cyclisation, wherein one or more are at ring carbon
Atom is by hetero atom such as O, N or S atom substitution.Heterocyclylalkyl preferably has 3,4,5,6 or 7 ring member nitrogen atoms.
Term " heterocycle " refers to the cyclic group containing hetero atom O, N or S, such as furans, thiophene, pyrroles, thiazole, miaow
Azoles, pyridine, pyridazine, pyrimidine, pyrazine, quinoline, isoquinolin, indoles, benzofuran, purine, acridine etc..
" 1- menaphthyls " refers to
" 2- menaphthyls " refers to
" indole methyl " refers to
" alkoxy " refers to-O- alkyl groups, and carbon atom number is generally 1~10.The example of alkoxy includes methoxy
Base, ethyoxyl, propoxyl group (e.g., n- propoxyl group and isopropoxy), t- butoxy etc..
" aryl " refers to aromatic carbocyclyl groups, including monocycle or polycyclic aromatic hydrocarbon such as phenyl, naphthalene, anthryl, phenanthryl etc..
" aryloxy group " refers to-O- aryl, and the concept of aryl is as described above, the most preferred example of aryloxy group is phenoxy group.
" halogen " includes fluorine, chlorine, bromine and iodine.
R in the compounds of this invention2Group can be raceme, it is possible to have optical activity, the present invention in R2Group
Preferably R configurations.
The compounds of this invention can be to prepare antitumor drug, and total preparation route is：
Each group R in the reaction equation1, R2, Z1And Z2Defined as described above, route one is phthalimide and chlorine
Ethyl acetate production (II-1), formula (II-1) react production (II-2) with alanine, and formula (II-2) is given birth to 8- aminoquinolines
An accepted way of doing sth (II-3), formula (II-3) and aryl Iod R production (II-4), formula (II-4) are reacted under the conditions of boron trifluoride ether
Production (II-5), formula (II-5) is reacted under the conditions of ethylenediamine generates formula (II)；Route two is formula (III-1) in SOCl2Make
Formula (III) is obtained by the reaction with methanol with lower.The formula (II) of route one and route two, formula (III)) compound is under peptide condensing agent point
Not and R1Production (I-1) compound, formula (I-1) compound saponification are acidified production (I-2) compound, formula (I-2) chemical combination again
Object is condensed production (I-3) compound, formula (I-3) under peptide condensing agent with the semicarbazide hydrochloride of borate or trifluoroacetate
Compound generates formula (IV) compound, last formula (IV) compound production under the conditions of hot ethyl acetate in acid condition
(V) compound.
The preparation method of the compounds of this invention described below：
R1, R2, Z1And Z2It is as defined above.
The preparation method of compound II includes following step：
1) chemical combination of formula (II-1) structure is obtained by the reaction with ethyl chloroacetate under triethylamine effect for phthalimide
Object；
2) compound of formula (II-1) structure and alanine are in Na2CO3And H2Production (II-2) structure under conditions of O
Compound；
3) compound of formula (II-2) structure is first in SOCl2Under the action of generate acyl chlorides, then with 8- aminoquinolines in alkali
The compound of production (II-3) under the conditions of property；
4) compound of formula (II-3) structure and aryl iodide production (II-4) under conditions of palladium and silver tetrafluoroborate
Compound；
5) chemical combination of the compound of formula (II-4) structure under conditions of boron trifluoride ether with methanol production (II-5)
Object；
6) compound of formula (II-5) structure generates the compound of formula (II) under conditions of ethylenediamine with methanol.
The preparation method of compound (III) includes following step：
The amino acid of formula (III-1) structure is in SOCl2The lower compound that formula (III) structure is obtained by the reaction with methanol of effect.
The preparation method of compound (I) includes following step：
1) formula (II) and formula (III)) shown in compound under peptide condensing agent with R1Production (I-1) compound；
2) compound of formula (I-1) structure occurs saponification and generates its sodium salt under alkaline condition, then in acid item
Compound (I-2) is generated under part；
3) formula (I-2) compound is condensed production under peptide condensing agent with the semicarbazide hydrochloride of borate or trifluoroacetate
(I-3) compound；
4) formula (I-3) compound generates formula (IV) compound under the conditions of isobutaneboronic acid.
5) formula (IV) compound generates formula (V) compound under the conditions of boiling ethyl acetate
Common peptide condensing agent is N in above-mentioned reaction, and N- dicyclohexyl-carbodiimides (are abbreviated as DCC), 1- (3- diformazans
Aminopropyl) -3- ethyl-carbodiimide hydrochlorides (being abbreviated as EDCHCl), 1- hydroxy benzo triazoles (being abbreviated as HOBt) or
Isobutyl chlorocarbonate.
The present inventor experiments prove that, the present invention in compound have good protease inhibition body work
Property and antitumor activity, part of compounds show preferable proteasome inhibition activity and antitumor work under nanomolar range
With having the application value in terms of preparing proteasome inhibitor or antitumor drug.Meanwhile the compound designed by the present invention
Preparation method yield is higher, simple for process, is suitably adapted for industrialized production.
Specific implementation mode
The synthesis of first part's compound
The preparation of the compound of the present invention can be implemented as follows：
One, the preparation of compound (II)
1, the preparation of N- ethyl acetate phthalimide II-1：
Phthalimide is dissolved in DMF, triethylamine is added, monoxone second is added dropwise into reaction system at 0 DEG C
Ester reacts 2 hours after being slowly increased to room temperature, reaction solution is poured into ice water, and filtering, filter cake is washed with ice water, vacuum drying
Obtain pure (Formula II -1) compound.
2, the preparation of the alanine II-2 of N- phthalyls Asia protection：
Compound II-1 and l-Alanine are dissolved in H2In O, Na is added2CO3Reaction 2 hours, add 1N HCl adjust pH value to
2, filtering, vacuum drying is up to pure (Formula II -2) compound.
3, the preparation of compound II-3：
Compound II-2 is dissolved in CH2Cl2In, SOCl is added2Condensing reflux 6 hours, removes solvent under reduced pressure.By 8- amino
Quinoline is dissolved in CH with DIPEA2Cl2In, CH is added dropwise at -20 DEG C2Cl2The acyl chlorides of dissolving is slowly increased to room temperature reaction overnight.Subtract
Solvent is evaporated off in pressure, and compound II-3 is obtained through column chromatography for separation.
3, the preparation of compound II-4：
Compound II-3 is dissolved in the tert-butyl alcohol, it is small that palladium, silver tetrafluoroborate and alkyl iodide, condensing reflux 24 is added
When, after being restored to room temperature, use CH2Cl2Dilution, is added triethylamine react 3 hours, crosses diatomite, solvent is removed under reduced pressure, through column layer
Analysis detaches to obtain compound II-4.
4, the preparation of compound II-5：
Compound II-4 is dissolved in heavy wall pressure bottle in MeOH, boron trifluoride ether solution is added dropwise, 100 DEG C were reacted
Night is added triethylamine stirring, removes solvent under reduced pressure, be dissolved in CH2Cl2Afterwards, pickling (10% hydrochloric acid), alkali cleaning (5% carbonic acid are used respectively
Hydrogen sodium) and saturated common salt washing, desiccant dryness (anhydrous sodium sulfate and anhydrous magnesium sulfate).Drier is filtered out, evaporated under reduced pressure is molten
Agent obtains compound II-5 through column chromatography for separation.
4, the preparation of compound II：
Compound II-5 is dissolved in MeOH, ethylenediamine is added, 70 DEG C of condensing refluxes react 5 hours, filtering, filtrate decompression
Solvent evaporated obtains compound II through column chromatography for separation.
Three, the preparation of compound (III)
By compound, (III-1 is dissolved in MeOH, and SOCl2 is added dropwise under ice salt bath, is warmed to room temperature overnight, is subtracted after being added dropwise
Press solvent evaporated to get compound III).
Three, the preparation of compound (I)
1, the preparation of compound I-1：
By R1- COOH is dissolved in CH2Cl2In, 1- hydroxy benzo triazoles (HOBt) are added, are reacted at -5 DEG C after ten minutes,
Peptide condensing agent (EDCHCl) is added, reacts 20 minutes, compound I or III is added, N, N- diisopropyls are added after ten minutes
Ethamine (DIPEA) is stirred overnight at room temperature after reacting half an hour.Reaction solution uses pickling (10% hydrochloric acid), alkali cleaning (5% carbon respectively
Sour hydrogen sodium) and saturated common salt washing, desiccant dryness (anhydrous sodium sulfate and anhydrous magnesium sulfate).Filter out drier, evaporated under reduced pressure
Solvent obtains compound I-1 through column chromatography for separation.
2, the preparation of compound I-2：
Compound I-1 is dissolved in MeOH, LiOHH is added2O and H2O removes MeOH under reduced pressure, adds 1N after reacting 3 hours
HCl adjusts pH value to 2, liquid separation is extracted with ethyl acetate, evaporated under reduced pressure solvent is up to compound I-2.
3, the preparation of compound I-3：
Compound I-2 is dissolved in CH2Cl2In, 1- hydroxy benzo triazoles (HOBt) are added, are reacted 10 minutes at -5 DEG C
Afterwards, peptide condensing agent (EDCHCl) is added, reacts 20 minutes, the hydrochloride or trifluoroacetate of borate is added, after ten minutes
N,N-diisopropylethylamine (DIPEA) is added, is stirred overnight at room temperature after reacting half an hour.Reaction solution uses pickling (10% respectively
Hydrochloric acid), alkali cleaning (5% sodium bicarbonate) and saturated common salt washing, desiccant dryness (anhydrous sodium sulfate and anhydrous magnesium sulfate).It filters out
Drier, evaporated under reduced pressure solvent obtain compound I-3 through column chromatography for separation.
4, the preparation of compound IV
Compound I-3 is dissolved in MeOH, isobutaneboronic acid, n-hexane and 1N HCl is added, reaction is overnight.Liquid separation is used
N-hexane phase is extracted in MeOH 2 times, then wash methanol phase 1 time with n-hexane, remove methanol under reduced pressure, use CH2Cl2Aqueous phase extracted 2
It is secondary, it is in neutrality with saturated common salt water washing organic phase to water phase.Evaporated under reduced pressure solvent obtains compound IV through column chromatography for separation.
5, the preparation of compound V
The amine containing glycol or acid are dissolved in ethyl acetate at 74 DEG C, compound IV is added, is cooled to 60 DEG C, reaction
3 hours, then it is cooled to 25 DEG C of reactions overnight.Filtering, vacuum drying obtain pure (Formula V) compound.
The compound of the present invention preparation process is described with the synthesis of particular compound below：
One, in formula (II) compound preparation：
1, the preparation of N- ethyl acetate phthalimide (compound II-1)
Phthalimide (7.36g, 50mmol) is dissolved in DMF (25mL), addition triethylamine (9mL,
65mmol), ethyl chloroacetate (5.7mL, 60mmol) is added dropwise at 0 DEG C into reaction system, after being slowly increased to room temperature, TLC detections
Reaction, 2h reactions terminate, reaction solution are poured into ice water, filter, and filter cake is washed with ice water, and vacuum drying obtains pure N- second
Acetoacetic ester phthalimide 8.67g, yield 79.1%, mp 81.4-83.6 DEG C.1H NMR (400MHz, CDCl3)δ1.44
(-CH3, t, J=7.1Hz, 3H), 4.48 (- CH2, q, J=7.1Hz, 2H), 7.80-7.85 (- Ph, m, 2H), 7.93-7.99 (-
Ph, m, 2H).MS(ESI)：m/z 220.1[M+H]+。
2, the preparation of the alanine (compound II-2) of N- phthalyls Asia protection：
Compound II-1 (21.9g, 100mmol) and l-Alanine (8.9g, 100mmol) are dissolved in H2In O (100mL),
Na is added2CO3(10.6g, 100mmol), TLC detection reactions, 2h reactions terminate, and add 1N HCl to adjust pH value to 2, filter, vacuum
Pure (Formula II -2) the compound 17.4g of drying, yield 79.3%, mp 145.8-146.6 DEG C.1H NMR (400MHz, CDCl3)
δ1.71(-CH3, d, J=7.4Hz, 3H), 5.02 (- CH, q, J=7.4Hz, 1H), 7.69-7.75 (- Ph, m, 2H), 7.82-
7.88 (- Ph, m, 2H).MS(ESI)：m/z 218.2[M-H]-。
3, the preparation of (S) -2- (phthalimide-based)-N- (8 quinolyl) propionamide (compound II-3)：
Compound II-2 (17.37g, 79.25mmol) is dissolved in CH2Cl2In (80mL), SOCl is added2(29mL,
396.25mmol) condensing reflux 6 hours, remove solvent under reduced pressure.By 8- aminoquinolines (11.4g, 79.25mmol) and DIPEA
(20.5g, 158.5mmol) is dissolved in CH2Cl2In (103mL), CH is added dropwise at -20 DEG C2Cl2The acyl chlorides of (31mL) dissolving, is added dropwise
After be slowly increased to room temperature reaction overnight.TLC detection reactions, remove solvent under reduced pressure, II-3 compounds are obtained through column chromatography for separation
21.2g, yield 77.42%, mp 180.0-181.9 DEG C.1H NMR (400MHz, CDCl3)δ1.98(-CH3, d, J=7.3Hz,
3H), 5.27 (- CH, q, J=7.5Hz, 1H), 7.42 (- Ph, dd, J1=4.2Hz, J2=8.3Hz, 1H), 7.51 (- Ph, s,
1H), 7.53 (- Py, d, J=9.0,1H), 7.65-7.85 (- Ph, m, 2H), 7.90 (- Ph, dt, J1=3.6, J2=7.1Hz,
2H), 8.15 (- Py, d, J=8.3Hz, 1H), 8.69 (- Ph, d, J=4.2Hz, 1H), 8.73 (- Py, dd, J1=4.7, J2=
8.9Hz, 1H), 10.33 (- CONH, s, 1H).MS(ESI)：m/z 346.0[M+H]+。
4, the preparation of (S) -2- amino -3- (4- (trifluoromethyl) phenyl) methyl propionate (IIa)
(1) (S) -2- (phthalimide-based)-N- (8- quinolyls) -3- (4- (trifluoromethyl) phenyl) propionamide
(II-4a) preparation
Compound II-3 (5.2g, 15mol) is dissolved in the tert-butyl alcohol (105mL), addition palladium (331mg,
1.5mmol), silver tetrafluoroborate (3.65g, 18.75mmol) and 4- iodine benzotrifluoride (6.12g, 22.5mmol), 85 DEG C are condensed back to
For 24 hours, TLC detection reactions after being warming up to room temperature, use CH to stream2Cl2(100mL) dilutes, and triethylamine (10mL) is added and stirs 3h, reaction
Liquid crosses diatomite, removes solvent under reduced pressure, and solid product 5.3g, yield 72.1%, mp 124.0-125.5 are obtained through column chromatography for separation
℃。1H NMR (400MHz, CDCl3)δ3.77-3.95(-CH2, m, 2H), 5.47 (- CH, dd, J1=6.9Hz, J2=9.7Hz,
1H), 7.39 (- Ph, dd, J1=4.3Hz, J2=8.3Hz, 1H), 7.42 (- Ph, d, J=8.1Hz, 2H), 7.49 (- Ph, d, J=
8.2Hz, 2H), 7.51 (- Ph, s, 1H), 7.53 (- Py, t, J=5.5Hz, 1H), 7.68-7.78 (- Ph, m, 2H), 7.78-
7.91 (- Ph, m, 2H), 8.12 (- Py, dt, J1=7.1Hz, J2=14.1Hz, 1H), 8.58 (- Ph, dd, J1=1.5Hz, J2
=4.2Hz, 1H), 8.67-8.79 (- Py, m, 1H), 10.28 (- CONH, s, 1H).MS(ESI)：m/z 487.1[M-H]-。
Above-mentioned steps preparation may be used in other similar compounds.
II-4b：Bis- (trifluoromethyl) benzene of iodo- 3, the 5- of II-3 and 1- are synthesized using the method for embodiment (1)；II-4c：It will
The iodo- Isosorbide-5-Nitraes of II-3 and 6--benzo dioxy alkane is synthesized using the method for embodiment (1)；II-4d：By II-3 and 2,4- dimethoxy iodine
Benzene is synthesized using the method for embodiment (1).
Particular compound and its property such as following table of synthesis.
(2) preparation of (S) -2- (phthalimide-based) -3- (4- (trifluoromethyl) phenyl) methyl propionate (II-5a)
Compound II-5a (2g, 4.1mmol) is dissolved in heavy wall pressure bottle in MeOH (94mL), trifluoro is slowly added dropwise
Change borate ether solution (5.2mL, 40.9mmol) reacts overnight at 100 DEG C, TLC detection reactions, addition triethylamine (8.6mL,
61.3mmol) stirring a period of time, removes solvent under reduced pressure, use CH2Cl2(30mL) dissolves, and uses pickling (10% hydrochloric acid), alkali respectively
Wash (5% sodium bicarbonate) and saturated common salt washing, desiccant dryness (anhydrous sodium sulfate and anhydrous magnesium sulfate).Drier is filtered out,
Evaporated under reduced pressure solvent obtains oil product 1.3g, yield 83.2% through column chromatography for separation.1H NMR (400MHz, CDCl3)δ3.55-
3.71(-CH2, m, 2H), 3.78 (- CH3, s, 3H), 5.18 (- CH, dd, J1=5.8Hz, J2=10.7Hz, 1H), 7.30 (- Ph,
D, J=8.0Hz, 2H), 7.46 (- Ph, d, J=8.0Hz, 2H), 7.67-7.75 (- Ph, m, 2H), 7.79 (- Ph, dt, J1=
3.6Hz, J2=7.1Hz, 2H).MS(ESI)：m/z 378.3[M+H]+。
Above-mentioned steps preparation may be used in other similar compounds.
II-5b：II-4b is synthesized using the method for embodiment (2)；II-5c：The method that II-4c is used into embodiment (2)
Synthesis；II-5d：II-4d is synthesized using the method for embodiment (2).
Particular compound and its property such as following table of synthesis.
(3) preparation of (S) -2- amino -3- (4- (trifluoromethyl) phenyl) methyl propionate (IIa)
Compound II-5a (745mg, 1.9mmol) is dissolved in MeOH (19mL), addition ethylenediamine (297mg,
4.9mmol), condensing reflux at 70 DEG C, TLC detection reactions, 5h reactions terminate, filter, filtrate decompression solvent evaporated, through column chromatography
Detach to obtain oily target compound 311mg, yield 62.4%.12.84 (- CH of H NMR (400MHz, DMSO) δ2, dd, J1=
7.7Hz, J2=13.3Hz, 1H), 2.95 (- CH2, dt, J1=9.5Hz, J2=19.0Hz, 1H), 3.59 (- CH3, s, 3H), 3.61
(- CH, d, J=6.9Hz, 1H), 7.40 (- Ph, t, J=11.9Hz, 2H), 7.59 (- Ph, t, J=21.6Hz, 2H).MS
(ESI)：m/z 248.1[M+H]+。
Above-mentioned steps preparation may be used in other similar compounds.
IIb：II-5b is synthesized using the method for embodiment (3)；IIc：I-5c is synthesized using the method for embodiment (3)；
IId：II-5d is synthesized using the method for embodiment (3).
Particular compound and its property such as following table of synthesis.
Two, in formula (III) compound preparation：
1, the preparation of glycine methyl ester hydrochloride (IIIa)
Compound IIIa (3g, 40mmol) is dissolved in MeOH (30mL), ice salt bath is cooled to -10 DEG C, slow under stirring
SOCl is added dropwise2(29mL, 400mmol) reacts 10min after completion of dropwise addition, removes ice salt bath, and overnight, TLC is detected for reaction at room temperature
Reaction is concentrated under reduced pressure, adds 20mLCH2Cl2, it is concentrated under reduced pressure repeatedly twice, is spin-dried for solvent, it is dry, obtain product 5g, yield
99.5%, product is not purified, is directly used in the next step.
Above-mentioned steps preparation may be used in the hydrochloride of used other amino acid methyl esters in the present invention.Compound
IIIb：It is synthesized using D- Cyclohexylglycines by the method for synthesis compound IIIa；Compound IIIc：By synthesis compound IIIa
Method using L- Cyclohexylglycines synthesize；Compound IIId：It is closed using phenylalanine by the method for synthesis compound IIIa
At.
Particular compound and its property such as following table of synthesis.
2, the preparation of L-O- methyl serines methyl ester hydrochloride (IIIe)
(1) preparation of BOC-L-O- methyl serines methyl esters (IIIe-1)
BOC-L- serine methylesters (5g, 22.8mmol) are dissolved in acetone (110mL), addition iodomethane (32mL,
524mmol) with silver oxide (8.2g, 35.4mmol), it is protected from light condensing reflux at 59 DEG C and stays overnight.TLC detection reactions, filtering subtract
Solvent is evaporated off in pressure, and oily target compound 1.8g, yield 34.5% are obtained through column chromatography for separation.1H NMR (400MHz, CDCl3)δ
1.43(-CH3, s, 9H), 3.32 (- CH3, s, 3H), 3.57 (- CH2, dd, J1=3.4Hz, J2=9.4Hz, 1H), 3.74 (- CH3,
D, J=6.3Hz, 3H), 3.78 (- CH2, dd, J1=3.1Hz, J2=9.4Hz, 1H), 4.35-4.44 (- CH, m, 1H), 5.28-
5.44 (- CONH, m, 1H).MS(ESI)：m/z 234.2[M+H]+。
(2) preparation of L-O- methyl serines methyl ester hydrochloride (IIIe)
Compound IIIe-1 (496mg, 2.1mmol) is dissolved in ethyl acetate (2.5mL), is added dropwise HCl's under ice bath
Ethyl acetate solution (5.2mL, 21.2mmol), reacts at room temperature, and TLC detection reactions, 2h reactions terminate, filter, filter cake vacuum
Drying pure products 351mg, yield 97.5%.1H NMR (400MHz, CDCl3)δ3.41(-CH3, s, 3H), 3.83 (- CH3,
S, 3H), 3.95 (- CH2, dd, J1=3.6Hz, J2=10.4Hz, 1H), 4.03 (- CH2, dd, J1=2.6Hz, J2=10.3Hz,
1H), 4.45 (- CH, s, 1H), 8.70 (- NH3 +, s, 3H).
3, the preparation of S- methyl-Lcysteines methyl ester hydrochloride (IIIf)
(1) preparation of S- methyl-Lcysteines (IIIf-1)
L-cysteine hydrochloride monohydrate (3.1g, 17.5mmol) is dissolved in MeOH (45mL), is added dropwise under ice bath
After reacting 1h, iodomethane (0.9mL, 13.mmol), heating is added dropwise in the methanol solution (11.2g, 62mmol) of 30% sodium methoxide
To room temperature reaction, TLC detection reactions, 2h reactions terminate, and with 10N HCl tune pH value to 5,40mL ether are added and stirs 10min, mistake
Filter, filter cake are washed with 60mL ether, are dried in vacuo, are obtained crude product 4.715g.
(2) preparation of S- methyl-Lcysteines methyl ester hydrochloride (IIIf)
S- methyl-Lcysteines (4.715g, 34.9mmol) are dissolved in MeOH (25mL), ice salt bath is cooled to -10
DEG C, SOCl is slowly added dropwise under stirring2(25mL, 348.8mmol) reacts 10min after completion of dropwise addition, removes ice salt bath, at room temperature
Overnight, TLC detection reactions are filtered, filter cake CH for reaction2Cl2Washing, vacuum drying is up to pure S- methyl-Lcysteines methyl esters
Hydrochloride 3.1g, yield 95.4%.1H NMR (400MHz, D2O) δ 4.44 (- CH, dd, J=7.7,4.6Hz, 1H), 3.90 (-
CH3, s, 3H), 3.23 (- CH2, dd, J=15.1,4.6Hz, 1H), 3.14-3.07 (- CH2, m, 1H), 2.18 (- CH3, s, 3H).
Three, in formula (I) compound preparation：
1, the preparation of (S)-N- (2,5- dichloro-benzoyl base) -3- (4- trifluoromethyls) methyl lactamines (I-1a)
2,5- dichlorobenzoic acids (90mg, 0.47mmol) and HOBt (92mg, 0.7mmol) are dissolved in CH2Cl2In (8mL),
React 10min at -10 DEG C, EDCHCl (135mg, 0.7mmol) be added and reacts 30min, be added compound IIa (116mg,
0.47mmol), DIPEA (151mg, 1.17mmol) is added after reacting 10min, reaction is warmed to room temperature overnight after reacting 20min.
TLC detection reaction, respectively with 10% hydrochloric acid solution (10mL), 5% NaHCO3Solution (10mL) and saturated salt solution (2 ×
It 10mL) washs, CH2Cl2Layer anhydrous Na2SO4Dry, filtering removes solvent under reduced pressure, obtains oily compound 166mg, yield
84.3%.Product is not purified, is directly used in the next step.
The product yield obtained in view of EDCHCl condensation methods is high, so other amino used in the present invention are unprotected
Amino acid methyl ester the preparation of the EDCHCl condensation methods described in embodiment 1 may be used, all methyl esters do not purify, directly use
In the next step.
Compound I-1b：It is synthesized using 2.5- dichlorobenzoic acids and IIb by EDCHCl condensation methods；Compound I-1c：It presses
EDCHCl condensation methods are synthesized using 2.5- dichlorobenzoic acids and IIc；Compound I-1d：2.5- is utilized by EDCHCl condensation methods
Dichlorobenzoic acid and IId synthesis.
(1), the preparation of (S)-N- (2,5- dichloro-benzoyl base) glycine methyl ester (I-1e)
2,5- dichlorobenzoic acids (7.6g, 40mmol) and HOBt (8.1g, 40mmol) are dissolved in CH2Cl2In (200mL),
React 10min at -10 DEG C, EDCHCl (11.5g, 60mmol) be added and reacts 30min, be added compound IIIa (5g,
40mmol), DIPEA (18.1g, 140mmol) is added after reacting 10min, reaction is warmed to room temperature overnight after reacting 20min.TLC is examined
Survey reaction, respectively with 10% hydrochloric acid solution (200mL), 5% NaHCO3Solution (200mL) and saturated salt solution (2 ×
It 200mL) washs, CH2Cl2Layer anhydrous Na2SO4Dry, filtering removes solvent under reduced pressure, obtains oily compound 9.32g, yield
88.9%.Product is not purified, is directly used in the next step.
Compound I-1f：It is synthesized using 2.5- dichlorobenzoic acids and IIIb by EDCHCl condensation methods；Compound I-1g：It presses
EDCHCl condensation methods are synthesized using 2.5- dichlorobenzoic acids and IIIc；Compound I-1h：It is utilized by EDCHCl condensation methods
2.5- dichlorobenzoic acids and IIIe synthesis；Compound I-1i：2.5- dichlorobenzoic acids and IIIf are utilized by EDCHCl condensation methods
Synthesis；Compound I-1j：It is synthesized using 2- pyrazine carboxylic acids and IIa by EDCHCl condensation methods；Compound I-1k：By EDCHCl
Condensation method is synthesized using 2- pyrazine carboxylic acids and IIc；Compound I-1l：5,6,7,8- tetrahydrochysene -1- are utilized by EDCHCl condensation methods
Naphthoic acid and IIc synthesis；Compound I-1m：It is synthesized using 5- methylisoxazole -3- formic acid and IIIa by EDCHCl condensation methods.
Compound I-1n：It is synthesized using 5- methyl -2- pyrazine carboxylic acids and IIId by EDCHCl condensation methods.
The amino acid methyl ester of used other amido protectings may be used described in embodiment (1) in the present invention
Prepared by EDCHCl condensation methods, all methyl esters do not purify, are directly used in the next step.
(2), the preparation of (S)-N- (Methoxyacetyl) phenyalanine methyl ester (I-1o)
Methoxyacetic acid (280mg, 3.13mmol) is dissolved in CH2Cl2SOCl is added dropwise at -10 DEG C in (6mL)2(0.25mL,
3.45mmol).Reaction 2h is warmed to room temperature after being added dropwise.Methoxyacetyl chloride solution is directly thrown in next step.By IIId (0.67g,
3.13mmol) it is dissolved in 3mL CH2Cl2In, triethylamine (1.58g, 15.65mmol) is added, methoxyacetyl chloride solution is added dropwise, instead
It should stay overnight.TLC detection reactions, are washed with water, Na2SO4It is dry, obtain oily target compound 0.69g, yield through column chromatography for separation
87.3%.
Compound I-1p：It is synthesized using 3- methoxypropionic acids and IIId by acyl chlorides condensation method；Compound I-1q：It contracts by acyl chlorides
It is legal to be synthesized using butyric acid and IIId；Compound I-1r：It is synthesized using ethylene-acetic acid and IIId by acyl chlorides condensation method；Compound
I-1s：It is synthesized using cyclopenta formic acid and IIId by acyl chlorides condensation method.
Institute in embodiment (2) may be used with alkyl acid in the amino acid methyl ester of used other amido protectings in the present invention
Prepared by the condensation method stated, all methyl esters do not purify, are directly used in the next step.
Particular compound and its property such as following table of synthesis.
2, the preparation of (S)-N- (2,5- dichloro-benzoyl base) -3- (4- trifluoromethyls) alanine (I-2a)
Compound I-1a (129mg, 0.31mmol) is dissolved with 2.5mLMeOH, LiOHH is added2O (39mg,
0.92mmol) and H2O (0.8mL), TLC are detected, and are reacted and are finished after 2h.It is spin-dried for organic phase, with ether (2 × 1mL) aqueous phase extracted,
It is 2~3 that hydrochloric acid to pH value, which is added dropwise, in water phase, generates a large amount of white solids, and ethyl acetate extracts, it removes solvent under reduced pressure, obtains white production
Product 106mg, yield 86.0%, mp 185.1-186.9 DEG C.13.02 (- CH of H NMR (400MHz, DMSO) δ2, dd, J1=
10.6Hz J2=13.8Hz, 1H), 3.30 (- CH2, dd, J1=4.6Hz, J2=13.9Hz, 1H), 4.68 (- CH, ddd, J1=
4.7Hz, J2=8.4Hz, J3=10.4Hz, 1H), 7.15 (- Ph, d, J=1.8Hz, 1H), 7.49 (- Ph, t, J=4.9Hz,
2H), 7.52 (- Ph, d, J=6.0Hz, 2H), 7.66 (- Ph, d, J=8.1Hz, 2H), 8.90 (- CONH, d, J=8.2Hz,
1H), 13.12 (- COOH, s, 1H).MS(ESI)：m/z 403.9[M-H]-。
The preparation of the method described in embodiment 2 may be used in the amino acid of used other amido protectings in the present invention.
Compound I-2b：I-1b is synthesized using the method for embodiment 2；Compound I-2c：By I-1c using embodiment 2
Method synthesizes；Compound I-2d：I-1d is synthesized using the method for embodiment 2；Compound I-2e：I-1e is used into embodiment 2
Method synthesis；Compound I-2f：I-1f is synthesized using the method for embodiment 2；Compound I-2g：I-1g is used into embodiment
2 method synthesis；Compound I-2h：I-1h is synthesized using the method for embodiment 2；Compound I-2i：By I-1i using implementation
The method of example 2 synthesizes；Compound I-2j：I-1j is synthesized using the method for embodiment 2；Compound I-2k：By I-1k using real
Apply the method synthesis of example 2；Compound I-2l：I-1l is synthesized using the method for embodiment 2；Compound I-2m：I-1m is used
The method of embodiment 2 synthesizes；Compound I-2n：I-1n is synthesized using the method for embodiment 2；Compound I-2o：I-1o is adopted
It is synthesized with the method for embodiment 2；Compound I-2p：I-1p is synthesized using the method for embodiment 2；Compound I-2q：By I-1q
It is synthesized using the method for embodiment 2；Compound I-2r：I-1r is synthesized using the method for embodiment 2；Compound I-2s：By I-
1s is synthesized using the method for embodiment 2.
Particular compound and its property such as following table of synthesis.
3, (S)-N- (2,5- dichloro-benzoyl base) -3- (4- trifluoromethyls) propionamide-D-Leu boric acid-(+) -
The preparation of australene alkane diol ester (I-3a)
Compound I-2a (340mg, 0.84mmol) and HOBt (218g, 1.67mmol) are dissolved in CH2Cl2In (18mL),
10min is reacted at -10 DEG C, and EDCHCl (321mg, 1.67mmol) is added and reacts 30min, be added (aR, 3aS, 4S, 6S,
7aR)-hexahydro -3a, 8,8- trimethyl-alpha- (2- methyl-propyls) -4,6- first bridges -1,3,2- benzo dioxy borine -2- methylamines
DIPEA (433mg, 3.35mmol), reaction is added after reacting 10min in 2,2,2- trifluoroacetates (317mg, 0.84mmol)
Reaction is warmed to room temperature after 20min overnight.TLC detection reaction, respectively with 10% hydrochloric acid solution (20mL), 5% NaHCO3It is molten
Liquid (20mL) and saturated salt solution (2 × 20mL) washing, CH2Cl2Layer anhydrous Na2SO4Dry, filtering removes solvent under reduced pressure,
Oily target compound 480mg, yield 87.6% are obtained through column chromatography for separation.1H NMR (400MHz, CDCl3)δ0.82(-CH3, s,
3H), 0.85 (- CH3, s, 6H), 1.16 (- CH2, dd, J1=7.8Hz J2=10.8Hz, 1H), 1.28 (- CH3, s, 3H),
1.32(-CH2, d, J=14.3Hz, 1H), 1.39 (- CH3, s, 3H), 1.41-1.52 (- CH, m, 1H), 1.63 (- CH, s, 1H),
1.81(-CH2, dd, J1=2.8Hz, J2=14.5Hz, 1H), 1.90 (- CH2, d, J=2.4Hz, 1H), 1.98-2.05 (- CH,
M, 1H), 2.12-2.23 (- CH2, m, 1H), 2.25-2.38 (- CH2, m, 1H), 3.19 (- CH, dd, J1=8.5Hz, J2=
13.7Hz, 1H), 3.23-3.31 (- CH2, m, 2H), 4.21-4.34 (- CH, m, 1H), 4.75-4.94 (- CH, m, 1H), 5.90
(- CONH, dd, J1=5.6Hz, J2=22.2Hz, 1H), 6.94 (- CONH, d, J=7.7Hz, 1H), 7.29-7.36 (- Ph, m,
2H), 7.41 (- Ph, dd, J1=4.2Hz, J2=7.8Hz, 2H), 7.51 (- Ph, s, 1H), 7.55 (Ph, dd, J1=3.7Hz,
J2=8.0Hz, 2H).MS(ESI)：m/z 653.2[M+H]+。
The preparation of the method described in embodiment 3 may be used in the amino acid of used other amido protectings in the present invention.
Compound I-3b：(aR, 3aS, 4S, 6S, 7aR)-hexahydro -3a, 8,8- trimethyls-are utilized by EDCHCl condensation methods
2,2,2- trifluoroacetate of alpha- (2- methyl-propyls) -4,6- first bridges -1,3,2- benzo dioxy borine -2- methylamines and I-2b are closed
At；Compound I-3c：(aR, 3aS, 4S, 6S, 7aR)-hexahydro -3a, 8,8- trimethyls-are utilized by EDCHCl condensation methods
2,2,2- trifluoroacetate of alpha- (2- methyl-propyls) -4,6- first bridges -1,3,2- benzo dioxy borine -2- methylamines and I-2c are closed
At；Compound I-3d：(aR, 3aS, 4S, 6S, 7aR)-hexahydro -3a, 8,8- trimethyls-are utilized by EDCHCl condensation methods
2,2,2- trifluoroacetate of alpha- (2- methyl-propyls) -4,6- first bridges -1,3,2- benzo dioxy borine -2- methylamines and I-2d are closed
At；Compound I-3e：(aR, 3aS, 4S, 6S, 7aR)-hexahydro -3a, 8,8- trimethyls-are utilized by EDCHCl condensation methods
2,2,2- trifluoroacetate of alpha- (2- methyl-propyls) -4,6- first bridges -1,3,2- benzo dioxy borine -2- methylamines and I-2e are closed
At；Compound I-3f：(aR, 3aS, 4S, 6S, 7aR)-hexahydro -3a, 8,8- trimethyls-are utilized by EDCHCl condensation methods
2,2,2- trifluoroacetate of alpha- (2- methyl-propyls) -4,6- first bridges -1,3,2- benzo dioxy borine -2- methylamines and I-2f are closed
At；Compound I-3g：(aR, 3aS, 4S, 6S, 7aR)-hexahydro -3a, 8,8- trimethyls-are utilized by EDCHCl condensation methods
2,2,2- trifluoroacetate of alpha- (2- methyl-propyls) -4,6- first bridges -1,3,2- benzo dioxy borine -2- methylamines and I-2g are closed
At；Compound I-3h：(aR, 3aS, 4S, 6S, 7aR)-hexahydro -3a, 8,8- trimethyls-are utilized by EDCHCl condensation methods
2,2,2- trifluoroacetate of alpha- (2- methyl-propyls) -4,6- first bridges -1,3,2- benzo dioxy borine -2- methylamines and I-2h are closed
At；Compound I-3i：(aR, 3aS, 4S, 6S, 7aR)-hexahydro -3a, 8,8- trimethyls-are utilized by EDCHCl condensation methods
2,2,2- trifluoroacetate of alpha- (2- methyl-propyls) -4,6- first bridges -1,3,2- benzo dioxy borine -2- methylamines and I-2i are closed
At；Compound I-3j：(aR, 3aS, 4S, 6S, 7aR)-hexahydro -3a, 8,8- trimethyls-are utilized by EDCHCl condensation methods
2,2,2- trifluoroacetate of alpha- (2- methyl-propyls) -4,6- first bridges -1,3,2- benzo dioxy borine -2- methylamines and I-2j are closed
At；Compound I-3k：(aR, 3aS, 4S, 6S, 7aR)-hexahydro -3a, 8,8- trimethyls-are utilized by EDCHCl condensation methods
2,2,2- trifluoroacetate of alpha- (2- methyl-propyls) -4,6- first bridges -1,3,2- benzo dioxy borine -2- methylamines and I-2k are closed
At；Compound I-3l：(aR, 3aS, 4S, 6S, 7aR)-hexahydro -3a, 8,8- trimethyls-are utilized by EDCHCl condensation methods
2,2,2- trifluoroacetate of alpha- (2- methyl-propyls) -4,6- first bridges -1,3,2- benzo dioxy borine -2- methylamines and I-2l are closed
At；Compound I-3m：(aR, 3aS, 4S, 6S, 7aR)-hexahydro -3a, 8,8- trimethyls-are utilized by EDCHCl condensation methods
2,2,2- trifluoroacetate of alpha- (2- methyl-propyls) -4,6- first bridges -1,3,2- benzo dioxy borine -2- methylamines and I-2m are closed
At；Compound I-3n：(aR, 3aS, 4S, 6S, 7aR)-hexahydro -3a, 8,8- trimethyls-are utilized by EDCHCl condensation methods
2,2,2- trifluoroacetate of alpha- (2- methyl-propyls) -4,6- first bridges -1,3,2- benzo dioxy borine -2- methylamines and I-2n are closed
At；Compound I-3o：(aR, 3aS, 4S, 6S, 7aR)-hexahydro -3a, 8,8- trimethyls-are utilized by EDCHCl condensation methods
2,2,2- trifluoroacetate of alpha- (2- methyl-propyls) -4,6- first bridges -1,3,2- benzo dioxy borine -2- methylamines and I-2o are closed
At；Compound I-3p：(aR, 3aS, 4S, 6S, 7aR)-hexahydro -3a, 8,8- trimethyls-are utilized by EDCHCl condensation methods
2,2,2- trifluoroacetate of alpha- (2- methyl-propyls) -4,6- first bridges -1,3,2- benzo dioxy borine -2- methylamines and I-2p are closed
At；Compound I-3q：(aR, 3aS, 4S, 6S, 7aR)-hexahydro -3a, 8,8- trimethyls-are utilized by EDCHCl condensation methods
2,2,2- trifluoroacetate of alpha- (2- methyl-propyls) -4,6- first bridges -1,3,2- benzo dioxy borine -2- methylamines and I-2q are closed
At.
Particular compound and its property such as following table of synthesis.
4, (S)-N- (2,5- dichloro-benzoyl base) -3- (4- trifluoromethyls) propionamide-D-Leu boric acid (IV-
1) preparation
Compound I-3a (317mg, 0.49mmol) is dissolved in the MeOH of 3mL, sequentially add isobutaneboronic acid (247mg,
2.43mmol), n-hexane (3mL) and 1N HCl (1.2mL, 1.2mmol), reaction is stirred overnight.TLC detection reactions, n-hexane
It is mutually extracted 2 times with MeOH (2 × 3mL), n-hexane (3mL) washs methanol phase 1 time, removes methanol, CH under reduced pressure2Cl2(2 × 2mL) extracts
Phase of fetching water 2 times, washs organic phase to water phase with saturated salt solution (3 × 5mL) and is in neutrality.Solvent is removed under reduced pressure, through column chromatography point
From obtaining pure products 193mg, yield 76.5%.1H NMR (400MHz, CDCl3)δ1.18(-CH3, s, 3H), 1.25 (- CH3, s,
3H), 2.13-2.41 (- CH2, m, 2H), 2.45-2.61 (- CH, m, 1H), 3.20-3.58 (- CH2, m, 2H), 3.58-3.71 (-
CH, m, 1H), 5.21-5.62 (- CH, m, 1H), 7.62-7.75 (- Ph, m, 4H), 7.84 (- Ph, t, J=13.5Hz, 3H).13C
NMR(CDCl3, 100MHz) and δ 22.67,27.21,31.90,35.60,51.28,54.80,125.37,125.55,128.92,
129.05,129.47,129.76,129.85,131.34,131.60,133.12,133.17,139.92,165.18,170.98.
MS(ESI)：m/z 517.1[M-H]-, calcd：518.1.HRMS(ESI)：calcd for C22H24BCl2F3N2NaO4[M+Na
]+541.1054 found 541.1118.
Above-mentioned method may be used in the synthesis of other boric acid compounds of the present invention.
Specific compound is as shown in the table.
Above-described boric acid compound can generate boric acid ester compound with reactions such as citric acids to be made as prodrug
With preparation method is described in the following example, but is not limited to this example：
5, the preparation of (S)-N- (2,5- dichloro-benzoyl base) acetamide-D-Leu boric acid diethanol amine ester (V)
Diethanol amine (160mg, 1.52mmol) is dissolved in 8mL ethyl acetate, is warming up to 74 DEG C, addition is dissolved in
The MLN2238 (500mg, 1.38mmol) of 1.5mL ethyl acetate, slow cooling react 3h, then slow cooling is to 25 DEG C to 60 DEG C
Overnight.TLC detection reactions, filtering, filter cake vacuum drying obtain pure products 557mg, yield 85.4%.Yield 93.6%.1H NMR
0.79 (- CH of (400MHz, DMSO) δ3, d, J=6.4Hz, 3H), 0.82 (- CH3, d, J=6.7Hz, 3H), 1.12-1.39 (-
CH2, m, 2H), 1.60 (- CH, s, 1H), 2.65-3.06 (- CH2, m, 4H), 3.14 (- CH, dd, J1=6.6Hz, J2=
10.8Hz, 1H), 3.30-3.73 (- CH2, m, 4H), 3.74-3.89 (- CH2, m, 2H), 6.58 (- NH, s, 1H), 6.98 (-
CONH, d, J=8.1Hz, 1H), 7.54 (- Ph, d, J=10.9Hz, 3H), 8.83 (- CONH, s, 1H)13C NMR (DMSO,
100MHz) 21.67 δ, 23.97,24.53,50.49,50.92,62.44,128.67,128.85,130.75,131.50,
131.61,137.83,165.25,167.73.HRMS (ESI)：calcd for C18H26BCl2N3NaO4[M+Na]+452.1289
found 452.1299.
Above-mentioned method synthesis may be used in other prodrug compounds of the present invention.
Second part protease inhibition body determination of activity
Proteasome inhibition activity
This patent (writes a Chinese character in simplified form Suc-LLVY-AMC, Suc tables using fluorescent peptide substrates Suc-Leu-Leu-Val-Tyr-AMC
Show succinyl group, AMC indicates 7- amide -4- methylcoumarins) come measure proteasome chymotrypsin sample enzymatic activity.
Proteasome used in this patent is human red blood cells 20S proteasomes, and enzyme, fluorogenic substrate and assay buffer are purchased
From Enzo companies.Experimental system is 16 μ L, wherein 8 μ L of substrate, 4 μ L (0.8ng) of proteasome, and ultimate density is 50 μM, drug
(inhibitor) 4 μ L, ultimate density are 2 × 10-6M~4.88 × 10-10M, the last one concentration are 0M, actual disposition a concentration of 8 ×
10-6M~1.95 × 10-9M, the last one concentration are 0M.Specific experiment process is as follows：
1, medicine ordinance：
Drug is weighed, DMSO is added and is dissolved to a concentration of 10-2M.With liquid-transfering gun draw 2 μ L add to 98 μ L DMSO obtain 2 ×
10-4M, then again from 2 × 10-48 μ L are drawn in M acute drugs, and 19g μ L H are added28 × 10 are obtained in O-6M utilizes same side
Method obtains 2 × 10-6M、5×10-7M、1.25×10-7M、3.12×10-8M、7.8×10-9M、1.95×10-9The drug of M concentration,
The last one concentration 0M is not dosing.
2, prepared by substrate：
25mg fluorescent peptide substrates are dissolved in 654 μ L DMSO, 50mM storing solutions are obtained, in -20 DEG C of preservations, are used
When dilute 500 times, 8 μ L are added in every part of sample so that the final concentration of substrate in reaction system is 50 μM.
3, prepared by reaction system：
20S proteasomes (2ng/ μ L) are diluted to the solution of a concentration of 8ng/ μ L with buffer solution, it is glimmering to be added to 384 holes
In light ELISA Plate, 4 μ L are added per hole, then 4 μ L samples to be tested are added in every hole, the use of marketed drug Bortezomib are positive control
Medicine reacts 15min at 37 DEG C.After reaction, 8 μ L fluorogenic substrates are added per hole, 37 DEG C are protected from light 1 hour, utilize
360nm/460nm fluorescence microplate readers (BMG LABTECH POLARstar OPTIMA Microplate Reader) detect fluorescence
Value.
4, data processing
The fluorescent value for calculating products therefrom under the drug effect of various concentration after deducting background, with GraphPad
Prism softwares calculate the IC that drug inhibits proteasome50Concentration.
The result of part of compounds such as following table：
| Compound number | IC50(nM) | Compound number | IC50(nM) | Compound number | IC50(nM) |
| IV-1 | 8.315 | IV-9 | 5.188 | IV-17 | 6.94 |
| IV-2 | 25.02 | IV-10 | 42.61 | IV-18 | 13.39 |
| IV-3 | 2.595 | IV-11 | 12.32 | IV-19 | 7.19 |
| IV-4 | 4.597 | IV-12 | 15.02 | V | 7.139 |
| IV-5 | 7.734 | IV-13 | 222.6 | Velcade | 7.035 |
| IV-6 | 82.03 | IV-14 | 26.24 | MLN2238 | 7.734 |
| IV-7 | 3.229 | IV-15 | 6.31 | MLN9708 | 13.06 |
| IV-8 | 9.956 | IV-16 | 8.47 |
The chemical structural formula of wherein Velcade and MLN9708 is：
Cell strain inhibitory activity
The detection liquid that this patent utilizes is that single Solution Cell Proliferation detects box, comes from Promega companies；Cell used is
U266, RPMI8226, ARH77.Experimental system is 110uL, wherein containing 90 μ L of cell suspension, detects 10 μ L of liquid, drug (inhibits
Agent) 10 μ L, final concentration of 4.54 × 10-8M~1.77 × 10-9M, the last one concentration are 0M, actual disposition a concentration of 5 ×
10-7M~1.95 × 10-8M, the last one concentration are 0M.Specific experiment process is as follows：
1, medicine ordinance：
Precise drug is added DMSO and is dissolved to 10-2M.With pipettor draw 1 μ L add to 199 μ L DMSO obtain 5 ×
10-5M, then from 5 × 10-5Drawn in M acute drugs 3.3 μ L add the RPMI1640 culture mediums of 326.7 μ L serum-frees obtain 5 ×
10-7M, 1.5 times of gradient dilutions, obtains 3.3 × 10-7M、2.2×10-7M、1.48×10-7M、9.87×10-8M、6.58×10- 8M、4.38×10-8M、2.92×10-8M、1.95×10-8The drug of M concentration, the last one concentration 0M are not dosing.
2, cell suspension configures：
After cell counts respectively, dilution configuration U266 is 1 × 104A/hole, RPMI8226 and ARH77 are 1 × 104A/
Hole.
3, prepared by reaction system：
90 μ L of cell suspension are added in 96 hole fluorescence ELISA Plates per hole, are incubated for 24 hours；Then 10 μ L are added in every hole and wait for test sample
Product are positive control drug using marketed drug Bortezomib, are incubated for 24 hours；After completion of the reaction, 10 μ L are added per hole and detect liquid, are incubated
2-3h, 490nm fluorescence microplate readers (BMG LABTECH POLARstar OPTIMA Microplate Reader) detect extinction
Degree.
4, data processing
The absorbance of products therefrom under various concentration drug effect after deducting background is calculated, it is soft with GraphPad Prism
Part calculates IC of the drug to cytotoxicity50Concentration.
The result of part of compounds such as following table：
| Number | RPMI8226 | ARH-77 | U266B1 | Number | RPMI8226 | ARH-77 | U266B1 |
| IV-1 | 233.7 | 98.15 | 100.4 | IV-12 | 41.16 | 35.52 | 58.38 |
| IV-2 | 186.6 | 154.60 | 217.3 | IV-15 | 4.567 | 5.726 | 6.041 |
| IV-3 | 17.84 | 10.06 | 9.42 | IV-16 | 7.326 | 9.039 | 11.58 |
| IV-4 | 37.78 | 14.58 | 18.66 | IV-17 | 5.613 | 7.875 | 8.509 |
| IV-5 | 55.32 | 65.50 | 52.15 | IV-18 | 8.170 | 12.37 | 6.426 |
| IV-7 | 97.03 | 69.46 | 65.8 | IV-19 | 3.985 | 6.869 | 2.764 |
| IV-8 | 8.99 | 9.10 | 6.75 | V | 43.45 | 28.06 | 34.93 |
| IV-9 | 8.97 | 8.85 | 6.45 | Velcade | 11.2 | 9.57 | 11.63 |
| IV-10 | 150.4 | 58.03 | 79.89 | MLN2238 | 55.32 | 65.50 | 52.15 |
| IV-11 | 43.44 | 29.26 | 30.26 | MLN9708 | 49.74 | 43.25 | 67.1 |
The therapeutic dose of designed compound can be according to the mode of administration, the purposes for the treatment of, patient in the present invention
The prescription of health status and doctor and determine.The concentration and proportion of compound in composition of medicine designed by the present invention will
Change with many factors, including administration route, dosage and chemical characteristic are (as dredged.For example, the change designed by the present invention
Closing object can be provided in for parenterai administration containing in about 0.1 to the aqueous physiological buffers of 10%w/v compounds.Some
Conventional dosage range is daily about 1 μ g/kg to 1g/kg.In a particular embodiment, dosage range is from about 10 μ daily
G/kg weight is to 100mg/kg weight.Dosage can according to administration route, the health status of patient, disease or the type of imbalance and into
Exhibition degree, the relative bioavailability of compound and excipient formula and change.Effective dosage can be from external or dynamic
The dose-effect curve of object model system is extrapolated.
Claims (5)
1. compound or pharmaceutically acceptable salt thereof is selected from：
2. compound or pharmaceutically acceptable salt thereof, the compound are
3. pharmaceutical composition, it includes pharmaceutical carrier and the compounds of claims 1 or 2, optionally simultaneously, respectively or sequentially with one
Kind or the combination of various other therapeutic agents.
4. purposes of the compound of claims 1 or 2 in preparing proteasome inhibitor.
5. the compound of claims 1 or 2 is preparing the purposes in treating disease medicament, it is characterised in that the disease is selected from：
Solid tumor and blood tumor, wherein solid tumor are selected from non-small cell lung cancer, Small Cell Lung Cancer, adenocarcinoma of lung, lung squamous cancer, cancer of pancreas, breast
Gland cancer, prostate cancer, liver cancer, cutaneum carcinoma, cell carcinoma, gastrointestinal stromal tumor or nasopharyngeal carcinoma, leukaemia, blood tumor are selected from more
Hair property myeloma, lymphoma mantle cell and histiocytic lymph cancer.
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| SG11201907945YA (en) * | 2017-02-28 | 2019-09-27 | Chia Tai Tianqing Pharmaceutical Group Co Ltd | Azetidine derivative |
| CN106916177B (en) * | 2017-03-23 | 2019-04-23 | 南京陵瑞医药科技有限公司 | A kind of deuterated dipeptide boronic acid or its ester type compound and its synthetic method and purposes |
| CN108794516A (en) * | 2017-04-26 | 2018-11-13 | 上海时莱生物技术有限公司 | Boric acid and boric acid ester compound and its preparation method and application |
| CN108929340B (en) * | 2017-05-22 | 2019-12-13 | 北京大学 | Proline boric acid compound and preparation method and application thereof |
| CN110540547A (en) * | 2018-05-28 | 2019-12-06 | 秦艳茹 | Synthesis and application of peptide borate compound |
| TWI810344B (en) * | 2018-08-02 | 2023-08-01 | 大陸商正大天晴藥業集團股份有限公司 | Boronate esters of azetidine derivatives |
| CN110790780B (en) * | 2018-08-02 | 2022-12-30 | 正大天晴药业集团股份有限公司 | Boron-containing azetidine derivatives |
| CN110950897B (en) * | 2019-12-12 | 2021-05-28 | 山东大学 | Histone deacetylase, protease double-target inhibitor, preparation method and application thereof |
| CN113105486B (en) * | 2021-02-24 | 2023-08-15 | 南京师范大学 | Boric acid ester compound and pharmaceutically acceptable salt thereof, and preparation method and application thereof |
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