CN105418663A - Chiral boric acid derivative and preparation method and application thereof - Google Patents

Chiral boric acid derivative and preparation method and application thereof Download PDF

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CN105418663A
CN105418663A CN201510835814.1A CN201510835814A CN105418663A CN 105418663 A CN105418663 A CN 105418663A CN 201510835814 A CN201510835814 A CN 201510835814A CN 105418663 A CN105418663 A CN 105418663A
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boric acid
carbon
phenyl
hydrogen
acid derivatives
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CN105418663B (en
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孙智华
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Shanghai University of Engineering Science
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    • 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
    • C—CHEMISTRY; METALLURGY
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    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
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    • C07B2200/07—Optical isomers
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    • Y02P20/00—Technologies relating to chemical industry
    • Y02P20/50—Improvements relating to the production of bulk chemicals
    • Y02P20/55—Design of synthesis routes, e.g. reducing the use of auxiliary or protecting groups

Abstract

The invention belongs to the field of organic chemistry, relates to a chiral boric acid derivative and a preparation method and application thereof and discloses the chiral boric acid derivative of the structure as shown in the general formula (I). The chiral boric acid derivative is formed by synthesizing unsaturated imine or ketone and diborane reagent with n-heterocyclic carbene ligand and alkali as catalysts. The boric acid derivative can be used for preparing medicine for treating cancer or diabetes as well as preparing other types of medicine by serving as a midbody. The synthesis method can increase the yield, improve stereoselectivity, lower the medicine preparation cost and simplify the synthesis route and has good economic benefits.

Description

A kind of chirality boric acid derivatives and its preparation method and application
The present patent application is application number 201310294398.X, July 12 2013 applying date, denomination of invention are: the divisional application of " chirality boric acid derivatives and its preparation method and application ".
Technical field
The present invention relates to derivative belonging to chirality boric acid and its preparation method and application.
Background technology
At occurring in nature, although there is not natural aminoboronic acid compounds, but boric acid base group wherein has the dis-guised of very special native amino carboxylic acid, thus allow it have spectacular biological activity, described is the compound with following structure with aminoboronic acid compounds like natural amino acid feature class:
Wherein: R is the various substituting groups of natural amino acid feature.
Aminoboronic acid is as the crucial pharmacophoric group of serinase Antagonism in recent years, more and more receives publicity in medicinal design.Due to physicochemical property and the space structure (having empty p track and less atomic radius) of boron atom uniqueness, aminoboronic acid can be designed to the various hydrolase inhibitor with vital role.As document Shenvi, al., US4499082 (1985) Shenvi etc. disclose peptidyl aminoboronic acid TM-1 compounds can as the inhibitor of proteolytic ferment, document Kentter, Shenvi, al., US5187157 (1993), US5242904 (1993), US5250720 (1993) Kentter, Shenvi discloses peptidyl aminoboronic acid TM-1 compounds equally can as the reversible inhibitor of Insulin-Like serine hydrolase, zymoplasm can be acted on, plasma kallikrein, plasminogen, document Kleeman, al., the aminoboronic acid TM-2 compounds that US5169841 (1992) .Kleeman discloses N end connection peptidyl has the activity suppressing feritin, Kettner, al., the aminoboronic acid TM-3 compounds that WO200102424 (2001) Kettner etc. disclose peptidyl has the effect suppressing hepatitis C virus, Kinder, al., US5106948 (1992) Kinder etc. reports N and holds the aminoboronic acid TM-2 compounds connecting peptidyl to have the effect of inhibition tumor cell growth, same Bachovchin, al., WO20070005991 (2007) Bachovchin etc. discloses peptidyl aminoboronic acid TM-4 compounds and has the effect suppressing fibroblast activated protein (FPA), this imply that this compounds has antineoplastic activity, the correlative study in later stage shows to have the potential quality suppressing carcinoma of the pancreas, Fleming, PaulE.al., the aminoboronic acid TM-5 compounds disclosed containing cyclopropyl such as WO2011123502 (2011) Fleming and PaulE. etc. has the effect that inhibition tumor cell increases, FDA have approved the first myelomatosis inhibitor B ortezomib containing aminoboronic acid in the recent period, and this new drug is for clinical.In addition, document is Snow a), R.et.al., J.Am.Chem.Soc., 1994,116,10860-10869.b) JackH.Lai, WilliamW.Bachovchin, et.al., J.Med.Chem.2007,50,2391-2398.c) GeorgeR.Lankas, et.al., Diabetes, 2005,54,2988-2994. report, the dried meat aminoboronic acid of peptidyl is the very effective inhibitor of two peptidyl dried meat aminases IV (DPP-4), can as the very promising medicine of type ii diabetes, and wherein to have completed III phase of FDA clinical for the PT-100 of U.S. Phenomix company.
Document:
Snow,R.et.al.,J.Am.Chem.Soc.,1994,116,10860-10869.：
JackH.Lai,WilliamW.Bachovchin,et.al.,J.Med.Chem.2007,50,2391-2398.
GeorgeR.Lankas,et.al.,Diabetes,2005,54,2988-2994.
K.Augustyns,P.VanderVeken,K.SentenandA.Haemers,CurrentMedicinalChemistry,2005,12,971-998.
PieterVanderVeken,AchielHaemersandKoenAugustyns,CurrentTopicsinMedicinalChemistry,2007,7,621-635.
DanielJDrucker,MichaelANauck,Lancet,2006；368:1696–705.
Study in chemosynthesis as aminoboronic acid and even the corresponding isomer of corresponding optical purity, still there is very large challenge its practicality and diversity aspect, particularly effectively, succinct stereoselective syntheses aspect.With the key intermediate of important serine hydrolase inhibitors--dried meat aminoboronic acid synthesize example, general employing multistep synthesis and the method split, be starting raw material mainly with Pinanediol diboron hexahydride ester and pyrroles or Pyrrolidine, as document E.ScottPriestley, CarlP.Decicco, US20030008828, (2003,1). report, Article 1 route synthetic method step is long, and yield is low, Article 2 route stereoselectivity is bad, alkali reagent used is to humidity sensitive, and operability is poor, and reaction formula is as follows:
Method at present about the asymmetric synthesis of aminoboronic acid is little, in fact only has two kinds of methods to be in the news.A kind of is the method for the Mattheson be widely used in academic and industry member, as document: DonaldS.MattesonandKizhakethilM.Sadhu, the report of J.Am.Chem.SOC.1981,103,5241-5242., utilize the Pinanediol diboron hexahydride ester containing chiral auxiliary to prepare chloroboric acid ester, then be further converted to aminoboronic acid, in the method, the side chain of aminoboronic acid is all derived by alkylboronic acids, which greatly limits their commercial possibility, reaction formula is as follows:
The Kettner utilization of Dupont drugmaker is made the method for electrophilic reagent to Matteson side chain and is expanded, as document SharadaJagannathan, TimothyP.Forsyth, andCharlesA.Kettner, the report of J.Org.Chem.2001,66,6375-6380., although enriched the diversity of aminoboronic acid to a certain extent, still there is significant limitation with regard to its reagent used and applicable scope.Reaction formula is as follows:
The above-mentioned method preparing aminoboronic acid all needs the synthesis through multistep, if directly ideal by the method for a step direct construction target compound, and about boron for carbon mix double bond addition report seldom, document GraceMann, KevinD.John, andR.TomBaker, Org.Lett., 2000,2 (14), 2105-2108.Baker etc. report a routine N-aryl aromatic aldehyde imines under platinum complex catalysis with Bis (catecholato) diboron (B 2cat 2) being obtained by reacting the aminoboronic acid ester of racemization, reaction formula is as follows:
On this basis, the method of asymmetric synthesis of direct chirality t-butyl sulfonamide induction, develop successfully by Ellman, see document MelissaA.Beenen, ChihuiAn, andJonathanA.Ellman, J.Am.Chem.Soc.2008, 130, the report of 6910 – 6911, the method utilizes tetramethyl ethylene ketone diboron hexahydride ester to be obtained by reacting chiral aminoboronic acid derivative with chirality tertiary butyl sulfenimide under the catalysis of (ICy) CuOtBu/ sodium tert-butoxide, although it has highly-solid selectively and the advantage higher to aliphatic chain alkyl substituted imine substrate yield, but just still there is the problem of two aspects in current the method, 1) the Cabbeen copper complex of the tertiary fourth oxygen copper of NHC is it used as catalyzer, this catalyzer can only be prepared and deposit in specific place (as glove box), prospect is used in the industrialization which has limited it, 2) there is limitation in the method for Ellman on substrate type, usually the yield for alkylamino boric acid good (yield: 74-88%), and test finds, the yield of arylamino boric acid is bad (yield: 52-61%), even can not get target product,
The core of the method for Ellman uses the boron ester addition reaction containing the t-butyl sulfonamide substrate of chiral sulfoxide prothetic group is carbene catalyzed to Cu (I)-azepine to enter row is verticalbody chemical induction.Since Wanzlick and Ofele nineteen sixty-eight reported first azepine Cabbeen (NHC) with metal complex since, existing many stable, this compounds separable are in the news successively, and this compounds usually obtains good effect when catalytic organometallic reacts, see document a) Herrmann, W.A.Angew.Chem.Int.Ed.2002,41,1290-1309.b) Zinn, F.K.; Viciu, M.S.; Nolan, S.P.Annu.Rep.Prog.Chem., Sect.B.2004,100,231-249.c) Scott, N.M.; The report of Nolan, S.P.Eur.J.Inorg.Chem.2005,1815-1828;
From giving the angle of electronics intensity, the azepine Cabbeen phosphine compound electrical with richness is more similar, is the 2-electron donor of a class neutrality.Can form complex compound with multiple transition metal, Coordinate property is similar to the organophosphorus ligand of electron rich, but the two stereochemical nature has again obvious difference, sees document: a) Scholl, M.; Trnka, T.M.; Morgan, J.P.; Grubbs, R.H.TetrahedronLett.1999,40,2247-2250.b) Scholl, M.; Ding, S.; Lee, C.W.; Grubbs, R.H.Org.Lett.1999,1,953-956.c) Trnka, T.M.; Grubbs, R.H.Acc.Chem.Res.2001,34,18-29.d) Huang, J.K.; Stevens, E.D.; Nolan, S.P.; Petersen, J.L.J.Am.Chem.Soc.1999,121,2674-2678.e) Ackermann, L.; Furstner, A.; Weskamp, T.; Kohl, F.J.; Herrmann, W.A.TetrahedronLett.1999, the report of 40,4787-4790.;
With the interaction of metal based on σ-key, metal/d track is relatively weak to the π retroactive effect of Cabbeen, is the neutral σ-part of a quasi-representative, sees document: a) Bielawski, C.W.; Grubbs, R.H.Angew.Chem.Int.Ed.2000,39,2903-2906.b) Bielawski, C.W.; Benitez, D.; Grubbs, R.H.Science, the report of 2002,297,2041-2044.;
Utilize the reaction of azepine Cabbeen (NHC) metal complex to catalyze all successfully to be applied to Heck, in Suzuki-Miyaura, Kumada, Sonogashira, Still, Negishi, Buchwald-Harting reaction, see document:
Herrmann,W.A.,Reisinger,C.P.,Siegler,M.,J.Organomet.Chem.1998,557,93-96.
Zhang,C.,Huang,J.,Trudell,M.L.,Nolan,S.P.,J.Org.Chem.,1999,64,3804-3805.
Grasa,G.A.,Nolan,S.P.,Org.Lett.,2001,3,119-122.
Huang,J.,Nolan,S.P.J.Am.Chem.Soc.,1999,121,9889-9890.b)Bohm,V.P.W.,Gstottmayr,C.W.K.,Weskamp,T.,Herrmann,W.A.,Angew.Chem.Int.Ed.2001,40,3387-3389.
Eckhardt,M.,Fu,G.C.,JAm.Chem.Soc.,2003,125,13642-13643.b)Aitenhoff,G.,Wuertz,S.,Glorius,F.TetrahedronLett.2006,47,2925-2928.
Grasa,G.A.,Nolan,S.P.,Org.Lett.,2001,3,119-122.
Hadei,N.,Kantchev,E.A.B.,Obrien,C.J.,Organ,M.G.,J.Org.Chem.,2005,70,8503-8507.
J.Huang,G.Grasa,S.P.Nolan,Org.Lett.,1999,1,1307-1309.b)Stauffer,S.R.,Lee,S.,Stambuli,J.P.,Hauck,S.I.,Hartwig,J.F.,Org.Lett.,2000,2,1423-1426.c)Marion,N.,Navarro,O.,Mei,J.,Stevens,E.D.,Scott,N.M.,Nolan,S.P.,J.Am.Chem.Soc.,2006,128,4101-4111
1993, report first case Cu (I)-azepine Cabbeen (NHC) complex compound { [(NHC) 2cu] [O 3sCF 3], see document: Arduengo, A.J.III., Dias, H.V.R., Calabrese, J.C., Davidson, F., Organometallics, the report of 1993,12,3405-3409.;
Document: Jurkauskas, V., Sadighi, J.P., Buchwald, S.L., Org.Lett., 2003,5,2417-2420. reports, Buchwald group with copper (I) with now to produce azepine Cabbeen and prepared single NHC and support copper (I) complex compound, prove that (I)-azepine Cabbeen (NHC) complex compound is typical two synergic agent to Cu, it is along with the increase of substituting group on nitrogen and metal combination ability, and its collaborative power also obviously increases.And it is used in the reduction of the carbon-carbon double bond of unsaturated carbonyl compounds, document: Kang-SangLee, Adil, R.ZhugralinandAmirH.Hoveyda, J.Am.Chem.Soc., 2009,131,7253-7255. reports, and Hoveyda group utilizes azepine Cabbeen to there is catalysis unsaturated carbonyl compounds and diborate reaction at metal salt-free, builds boric acid ester carbonyl compound.
Make a general survey of the construction process of aminoboronic acid, the utilization that azepine Cabbeen itself and copper complex thereof are mixed in double bond addition reaction to carbon at catalysis diboron hexahydride reagent, other research groups up to the present, the certain vacancy all existed from the mechanism of reaction to methodology and not exploration are clearly local, particularly azepine Cabbeen is as the research and development chirality azepine carbone catalyst stereoselective structure chiral aminoboronic acid research aspect of the reaction mechanism of small molecules catalysis, and this area research directly will promote such compound library structure and the multifarious development of synthetic method, thus to the research and development of new drug, there is the important effect of extremely important effect.
Summary of the invention
The present invention is 201310294398.X (title: " chirality boric acid derivatives and its preparation method and application ", July 12 2013 applying date) divisional application, its objective is and apply for a patent (application number: on basis 201210194758.4) previous, continue to disclose a kind of multifarious chiral aminoboronic acid derivative and its preparation method and application, to overcome the above-mentioned defect that prior art exists, meet the needs of association area development.
Multifarious chiral aminoboronic acid derivative of the present invention, for having the chemical combination of structure shown in formula I
Wherein:
R 1and R 2combine for catechu phenolic ester, pinacol ester, dimethylamino ester or (1S, 2S, 3R, 5S)-(+)-2,3-pinine glycol (Pinanediol) ester; Be preferably catechu phenolic ester.
R 3be selected from hydrogen, the straight or branched alkyl of C1-C12, the cycloalkyl of the C1-C12 straight or branched alkyl of replacement or the cycloalkyl group of 3-12 carbon or the C3-C12 of replacement, phenyl or substituted-phenyl, fragrant heterocycle or replacement virtue heterocycle;
Preferably, R 3for the C1-C12 straight or branched alkyl of the straight or branched alkyl of hydrogen or C1-C12, replacement, 1 phenyl or substituted-phenyl.
X is
R 5for hydrogen, the straight or branched alkyl containing 1-12 carbon, the alkylene containing 2-6 carbon, alkynes base containing 2-6 carbon, aromatic ring yl, aromatic heterocyclic or halogen, amido or substituted amido.
Preferably, R 5for the straight-chain paraffin base of hydrogen, a 1-12 carbon, a 3-12 carbon naphthene alkyl, branched alkane alkyl containing 3-12 carbon; or hydroxyl, sulfydryl, halogen substiuted containing the straight-chain paraffin base of 1-12 carbon atom, a 3-12 carbon naphthene alkyl or the branched alkane alkyl containing 3-12 carbon; or amido; or phenyl, substituted-phenyl, nitrogenous aromatic heterocyclic replace amido, or band protecting group amido.
R 7for hydrogen or the straight or branched alkyl containing 1-12 carbon.
Preferred, R 3for hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl, phenyl, pyridyl, pyrimidyl, tetrahydro pyridyl;
R 4for terf-butylsulfinyl; R 7for hydrogen or methyl;
R 5for hydrogen, methyl, ethyl, propyl group, butyl, methylol, hydroxyethyl, hydroxypropyl, phenmethyl, phenyl, aminomethyl phenyl, fluorophenyl, chloro-phenyl-, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, pyridyl, methylamino, ethylamino-.
Preferably, R 4for terf-butylsulfinyl, and: work as R 3for hydrogen and R 5during for hydrogen, R 7for hydrogen or methyl; Work as R 3for methyl and R 5during for hydrogen, R 7for methyl; Work as R 3for hydrogen and R 5during for aminomethyl phenyl, R 7for methyl; Work as R 3for hydrogen and R 5during for phenyl, R 7for phenyl
Preferred, described multifarious chirality boric acid derivatives is:
The preparation method of formula I compound of the present invention, comprises the steps:
Under azepine carbene precursor and base catalysis, by the α as shown in general formula (II '), α shown in β-unsaturated group with imine moiety or general formula (III '), alpha, beta-unsaturated ketone and diboron hexahydride reagent carry out stirring reaction in protic solvent, temperature of reaction is 15-30 DEG C, reaction times is 1 ~ 48 hour (being preferably 24-48 hour), then collection type (II) or (III) compound from reaction product;
In reacted mixture, add diluted ethyl acetate, and wash organic layer; Be extracted with ethyl acetate water layer again, merge organic layer and dry filter, concentrating under reduced pressure; Product carries out chromatography purification with silica gel or with the silica gel of water inactivation.
Reaction expression is as follows:
R 1~ R 7definition the same;
Described alkali is selected from sodium tert-butoxide, sodium carbonate, salt of wormwood, triethylamine, 1,5-diaza-bicyclo [5,4,0] hendecene-5, cesium fluoride, cesium carbonate or sodium hydride;
Described protic solvent selects methyl alcohol, ethanol, Virahol, tert-pentanol, difluoroethanol, trifluoroethanol, difluoro methyl alcohol, trifluoro methyl alcohol, thiomethyl alcohol, sulfur alcohol, isopropyl mercaptan, water and mixed solvent thereof etc.;
Described azepine carbene precursor is the compound with following chemical structure:
Wherein: R 6represent do not replace and replace the alkyl of 1-6 carbon, the alkoxyl group of 1-6 carbon of replacement, halogen, nitro, amino, replacement or the also benzene of ring, aromatic ring or fragrant heterocycle etc.; Preferably hydrogen, 3-fluorine, 3-nitro, 3-methyl, 3-methoxyl group or benzo; M, Q are nitrogen or carbon; R 7generation table 1the carbene alkyl of-8 carbon alkyl, 1-8, the alkynes base of a 1-8 carbon or aryl; X -represent fluorine, chlorine, bromine or iodine ion;
Ar 1represent phenyl, substituted-phenyl or aromatic heterocyclic, the substituting group of substituted-phenyl is methyl, fluorine, methoxyl group, cyano group or nitro; Aromatic heterocyclic is pyridyl, 6-picolyl, naphthyl, pyrazinyl, pyrryl, thienyl or pyrimidyl;
Wherein, preferred azepine carbene precursor is:
The preparation method of described azepine carbene precursor, can refer to following patent (patent name: multifarious aryl imidazoles quaternary ammonium salt and its preparation method and application, application number: 201210195065.7).
Wherein, the chemical structure of representational α, β-undersaturated imines II ' is:
Described diboron hexahydride reagent (boric acid ester) is for having the compound such as formula structure shown in B:
Wherein: R 1, R 2definition same as above.
Described diboron hexahydride reagent can commercialization buying.
Preferably, described diboron hexahydride reagent is selected from catechu phenolic ester, pinacol ester, dimethylamino ester, (1S, 2S, 3R, 5S)-(+)-2,3-pinine glycol (Pinanediol) ester; Concrete structure is as follows:
The mol ratio of each component is as follows:
Compound I ': diboron hexahydride reagent: azepine carbenes: alkali=1: 1 ~ 3: 0.05 ~ 0.2: 0.05 ~ 0.2;
Multifarious chiral aminoboronic acid of the present invention, may be used for the medicine preparing treatment tumour or diabetes, also can as the various medicine (tumour, type-II diabetes, the third liver, virus etc.) with critical treatment effect of intermediate.
Beneficial effect of the present invention is: described multifarious chirality boric acid derivatives, and wherein preparing involved chemical compound lot by the present invention is that other synthetic methods cannot be prepared, for new drug research provides abundant the type compound library at present; Yield and stereoselectivity can be improved, the preparation cost of such medicine can be reduced and simplify synthetic route.The economic benefit had.
Embodiment
Universal method 1:
By 0.2mmol Cabbeen azepine precursor and ligand L-08 ' (0.1eq.), 0.2mmol cesium carbonate (0.1eq.), 2mmol α, β-undersaturated imines or ketone (1eq.), 2mmol boric acid ester (1eq.) and solvent methanol (20ml), add in reaction flask, reaction solution is light yellow, at 15 ~ 30 DEG C, stir 24-48hr; Reaction process is monitored with TLC.Add EA (30ml) dilution after reaction terminates, and use K 2cO 3washing organic layer.Use EA (2 × 30ml) aqueous layer extracted afterwards.Merge organic layer Na 2sO 4drying, filters, concentrating under reduced pressure.Product silica gel or carry out column chromatography for separation with the silica gel of water inactivation, developping agent uses petrol ether/ethyl acetate system.
Methyl alcohol can use ethanol, Virahol, tert-pentanol, difluoroethanol, trifluoroethanol, difluoro methyl alcohol, trifluoro methyl alcohol, thiomethyl alcohol, sulfur alcohol, isopropyl mercaptan, water or said mixture to replace.
Embodiment 1
Add the imines Compound28 ' of 318mg (2mmol), adopt universal method 1, react 24 hours.Reaction mixture is by the silica gel crossed with water inactivation through row column chromatography purification, and developping agent is petrol ether/ethyl acetate system.Products therefrom is proterties is pale yellow oil 494mg (yield86%) at ambient temperature; 1hNMR (400MHz, DMSO-d 6, δ): 7.52 (d, J=9.6Hz, 1H), 5.97 (dd, J 1=9.6Hz, J 2=13.6Hz, 1H), 4.94 (m, 1H), 1.46 (d, J=7.6Hz, 1H), 1.18 (s, 12H), 1.13 (s, 9H); 13cNMR (100MHz, DMSO-d 6, δ): 129.5,104.4,83.3,56.0,25.1,22.9,12.5; MS (ESI-TOF) m/z:288.2 [M+H] +.
Embodiment 2
Add the imines Compound29 ' of 346mg (2mmol), adopt universal method 1, react 24 hours.Reaction mixture is by the silica gel crossed with water inactivation through row column chromatography purification, and developping agent is petrol ether/ethyl acetate system.Products therefrom is proterties is pale yellow oil 536mg (yield89%) at ambient temperature; 1hNMR (400MHz, CDCl 3, δ): 6.05 (dd, J 1=10.0Hz, J 2=13.6Hz, 1H), 5.12 (m, 1H), 4.96 (d, J=10.4Hz, 1H), 1.80 (t, J=7.2Hz, 1H), 1.25 (s, 21H), 1.08 (d, J=7.2Hz, 3H); 13cNMR (100MHz, CDCl 3, δ): 126.5,114.8,83.2,56.2,24.7,24.7,22.5,18.8,15.7; MS (ESI-TOF) m/z:302.2 [M+H] +.
Embodiment 3
Add the imines Compound30 ' of 374mg (2mmol), react 24 hours.Reaction mixture is by the silica gel crossed with water inactivation through row column chromatography purification, and developping agent is petrol ether/ethyl acetate system.Products therefrom is proterties is pale yellow oil 573mg (yield91%) at ambient temperature; 1hNMR (400MHz, CDCl 3, δ): 5.98 (dd, J 1=10.4Hz, J 2=14.0Hz, 1H), 5.14 (d, J=14.0Hz, 1H), 5.01 (d, J=10.0Hz, 1H), 1.24 (s, 9H), 1.23 (s, 12H), 1.05 (s, 6H); 13cNMR (100MHz, CDCl 3, δ): 125.3,120.5,83.2,56.2,24.9,24.6,24.5,24.4,22.5; MS (ESI-TOF) m/z:316.2 [M+H] +.
Embodiment 4
Add the imines Compound31 ' of 498mg (2mmol), adopt universal method 1, react 24 hours.Reaction mixture is by the silica gel crossed with water inactivation through row column chromatography purification, and developping agent is petrol ether/ethyl acetate system.Products therefrom is proterties is pale yellow oil 643mg (yield90%) at ambient temperature; 1hNMR (400MHz, CDCl 3, δ): 7.35 (d, J=8.0Hz, 2H), 7.18 (d, J=8.0Hz, 2H), 5.44 (t, J=8.0Hz, 1H), 4.86 (s, 1H), 2.37 (s, 3H), 1.71 (dd, J 1=4.8Hz, J 2=8.0Hz, 2H), 1.27 (s, 9H), 1.24 (s, 12H); 13cNMR (100MHz, CDCl 3, δ): 138.0,137.9,133.3,129.5,129.0,110.4,83.3,55.9,24.8,24.8,22.7,21.3; MS (ESI-TOF) m/z:358.3 [M+H] +.
Embodiment 5
(1) compound of Example 1 ~ 4 carries out DPIV suppression detection, and detection method is: by sample dissolution (pH=2) in 0.01M hydrochloric acid soln, be formulated as the solution of concentration 1mg/10 μ l.Again by the damping fluid of sample and 990 μ lpH=8 (containing 0.1mol/L hydroxyethyl piperazine second thiosulfonic acid HEPES and 0.14mol/LnaCl), mixed solution kept at room temperature overnight.Damping fluid (the same) dilution of 20 μ l concentration 2.5 μm ol/L DPP IV (DPIV) solution 40mlpH=8.Substrate is the L-Ala-L-Pro-p-Nitroaniline of concentration 0.1mg/ml.Substrate and enzyme are placed in 96 orifice plates, and at room temperature hatch 5 minutes in shaking table after adding sample, then leave standstill 5 minutes, and 410nm light detects, and contrasts with blank group.
(2) compound of Example 1 ~ 4, carries out the detection of FAP suppression by 96 well plate method.
Result as table 1.
table 1
Embodiment compound IC 50(μM)DPIV(pH＝8.0) FAP IC 50(μM)
1 44 0.51
2 51 0.62
3 51 0.52
4 34 0.48

Claims (10)

1. a chirality boric acid derivatives, is characterized in that, structural formula is such as formula shown in (I):
Wherein, R 1and R 2combine for catechu phenolic ester, pinacol ester, dimethylamino ester or (1S, 2S, 3R, 5S)-(+)-2,3-pinane diol ester;
R 3for the straight-chain paraffin base of hydrogen, a 1-12 carbon, a 3-12 carbon naphthene alkyl, branched alkane alkyl containing 3-12 carbon, or hydroxyl, sulfydryl, halogen substiuted containing the straight-chain paraffin base of 1-12 carbon atom, a 3-12 carbon naphthene alkyl or the branched alkane alkyl containing 3-12 carbon, or phenyl, substituted-phenyl;
X is
R 4for terf-butylsulfinyl, benzyl, alkanoyloxy, aryl acyloxy, p-methylphenyl alkylsulfonyl, p-methoxyphenyl or p-nitrophenyl alkylsulfonyl;
R 5for the straight-chain paraffin base of hydrogen, a 1-12 carbon, a 3-12 carbon naphthene alkyl, branched alkane alkyl containing 3-12 carbon, or hydroxyl, sulfydryl, halogen substiuted containing the straight-chain paraffin base of 1-12 carbon atom, a 3-12 carbon naphthene alkyl or the branched alkane alkyl containing 3-12 carbon, or amido, or phenyl, substituted-phenyl, nitrogenous aromatic heterocyclic replace amido, or band protecting group amido;
R 7for hydrogen or the straight or branched alkyl containing 1-12 carbon.
2. chirality boric acid derivatives according to claim 1, is characterized in that, described R 1and R 2combine for catechol;
Described R 3for hydrogen, methyl, ethyl, propyl group, sec.-propyl, butyl or phenyl;
Described R 4for terf-butylsulfinyl; Described R 7for hydrogen or methyl;
Described R 5for hydrogen, methyl, ethyl, propyl group, butyl, phenmethyl, phenyl or aminomethyl phenyl.
3. chirality boric acid derivatives according to claim 1, is characterized in that, described R 3for hydrogen or methyl, R 5for hydrogen, phenyl or aminomethyl phenyl, R 7for hydrogen, methyl or phenyl; Described R 4for terf-butylsulfinyl.
4. the chirality boric acid derivatives described in claim 1 or 3, is characterized in that, is selected from following compound:
5. the chirality boric acid derivatives described in any one of claim 1-4, preparation method, it is characterized in that, comprise the steps:
Under azepine carbene precursor and base catalysis, by the α as shown in general formula (II '), α shown in β-unsaturated group with imine moiety or general formula (III '), alpha, beta-unsaturated ketone and diboron hexahydride reagent react in protic solvent, then the compound of collection type (II) or (III) from reaction product; Reaction expression is as follows:
Temperature of reaction is 15 DEG C ~ 30 DEG C, and the reaction times is 1 ~ 48 hour, wherein R 1-R 7definition as described in Claims 1 to 4;
The amount ratio of described imine compound or ketone, diboron hexahydride reagent, azepine carbene precursor and alkali is 1:1 ~ 3:0.05 ~ 0.2:0.05 ~ 0.2;
R 1, R 2, R 3, R 4, R 5and R 6definition with claim 1.
6. the preparation method of chirality boric acid derivatives described in claim 5, it is characterized in that, described protic solvent selects methyl alcohol, ethanol, Virahol, tert-pentanol, difluoroethanol, trifluoroethanol, difluoro methyl alcohol, trifluoro methyl alcohol, thiomethyl alcohol, sulfur alcohol, isopropyl mercaptan, water and mixed solvent thereof.
7. the preparation method of chirality boric acid imine derivative described in claim 5, is characterized in that, described azepine carbene precursor is selected from following compound:
Described alkali is cesium carbonate, salt of wormwood or sodium carbonate.
8. the preparation method of chirality boric acid imine derivative described in claim 5, is characterized in that, add diluted ethyl acetate, and wash organic layer in reacted mixture; Be extracted with ethyl acetate water layer again, merge organic layer and dry filter, concentrating under reduced pressure; Product carries out chromatography purification with silica gel or with the silica gel of water inactivation.
9. the chirality boric acid derivatives described in Claims 1 to 4 is for the preparation of the medicine for the treatment of diabetes or tumour.
10. intermediate prepared by the medicine that the chirality boric acid derivatives described in Claims 1 to 4 is used for the treatment of diabetes or tumour.
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Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0354522A1 (en) * 1988-08-12 1990-02-14 Hoechst Aktiengesellschaft Use of alpha-aminoboronic acid derivatives in prevention and treatement of viral diseases
CN103030656A (en) * 2011-09-30 2013-04-10 北京大学 Synthetic method of proteasome inhibitor bortezomib and analogs

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
EP0354522A1 (en) * 1988-08-12 1990-02-14 Hoechst Aktiengesellschaft Use of alpha-aminoboronic acid derivatives in prevention and treatement of viral diseases
CN103030656A (en) * 2011-09-30 2013-04-10 北京大学 Synthetic method of proteasome inhibitor bortezomib and analogs

Non-Patent Citations (5)

* Cited by examiner, † Cited by third party
Title
HWANJONG JANG ET AL: "Highly Selective Methods for Synthesis of Internal Vinylboronates through Efficient NHC Cu-Catalyzed Hydroboration of Terminal Alkynes. Utility in Chemical Synthesis and Mechanistic Basis for Selectivity", 《J. AM. CHEM. SOC.》 *
KANG-SANG LEE ET AL: "Efficient C-B Bond Formation Promoted by N-Heterocyclic Carbenes: Synthesis of Tertiary and Quaternary B-Substituted Carbons through Metal-Free Catalytic Boron Conjugate Additions to Cyclic and Acyclic α,β-Unsaturated Carbonyls", 《J. AM. CHEM. SOC.》 *
KUN WEN ET AL: "Improving Carbene−Copper-Catalyzed Asymmetric Synthesis of α-Aminoboronic Esters Using Benzimidazole-Based Precursors", 《J. ORG. CHEM.》 *
MELISSA A. BEENEN ET AL: "Asymmetric Copper-Catalyzed Synthesis of Amino Boronate Esters from N-tert-Butanesulfinyl Aldimines", 《J. AM. CHEM. SOC.》 *
MING GAO ET AL: "sp2-sp3 Hybridized Mixed Diboron: Synthesis, Characterization, and Copper-Catalyzed β-Boration of α,β-Unsaturated Conjugated Compounds", 《ORG. LETT.》 *

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