CN103483363A

CN103483363A - Diverse chiral amino boric acid, preparation method and application thereof

Info

Publication number: CN103483363A
Application number: CN201210194758.4A
Authority: CN
Inventors: 孙智华; 范尔康
Original assignee: Shanghai Sai Jia Chemicals Co Ltd
Current assignee: Shanghai Sai Jia Chemicals Co Ltd
Priority date: 2012-06-13
Filing date: 2012-06-13
Publication date: 2014-01-01
Anticipated expiration: 2032-06-13
Also published as: CN103483363B

Abstract

The present invention discloses a diverse chiral amino boric acid, a preparation method and an application thereof, wherein the diverse chiral amino boric acid is a compound represented by a formula (I) or a formula (II). The diverse chiral amino boric acid has the following characteristics that: the library containing rich compounds with the type is provided for researches on new drugs, a yield and stereoselectivity can be increased, the preparation cost of the class 2 drugs can be reduced, the synthesis route of the class 2 drugs can be simplified, and good economic benefits are provided.

Description

Multifarious chiral aminoboronic acid and its preparation method and application

Technical field

The present invention relates to belong to chiral aminoboronic 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 natural aminocarboxylic acid, thereby allow it have spectacular biological activity, the aminoboronic acid compounds is the compound with following structure like described and natural amino acid feature class:

Wherein: the various substituting groups that R is the natural amino acid feature.

Alpha-amino boronic acid, as the crucial pharmacophoric group of serinase Antagonism, more and more receives publicity in medicinal design in recent years.Due to physicochemical property and the space structure (having empty p track and less atomic radius) of boron atom uniqueness, alpha-amino boronic acid can be designed to the various hydrolase inhibitors with vital role.As document Shenvi, al., the announcement peptidyl aminoboronic acid TM-1 compounds such as US4499082 (1985) Shenvi can be used as the inhibitor of proteolytic ferment, document Kentter, Shenvi, al., US5187157 (1993), US5242904(1993), US5250720(1993) Kentter, Shenvi discloses the reversible inhibitor that peptidyl aminoboronic acid TM-1 compounds can be used as the Insulin-Like serine hydrolase equally, can act on zymoplasm, plasma kallikrein, plasminogen, document Kleeman, al., the aminoboronic acid TM-2 compounds that US5169841 (1992) .Kleeman discloses N end connection peptidyl has the activity that suppresses feritin, Kettner, al., the aminoboronic acid TM-3 compounds of the announcement peptidyls such as WO200102424 (2001) Kettner has the effect that suppresses hepatitis C virus, Kinder, al., US5106948 (1992) Kinder etc. has reported that the aminoboronic acid TM-2 compounds of N end connection peptidyl has the effect of inhibition tumor cell growth, same Bachovchin, al., WO20070005991 (2007) Bachovchin etc. has disclosed peptidyl aminoboronic acid TM-4 compounds and has had the effect that suppresses fibroblast activated protein (FPA), this is indicating that this compounds has antineoplastic activity, the correlative study in later stage shows to have the potential quality that suppresses carcinoma of the pancreas, Fleming, Paul E.al., WO2011123502 (2011) Fleming and Paul E. etc. have disclosed the aminoboronic acid TM-5 compounds that contains cyclopropyl and have had the effect that inhibition tumor cell increases, FDA has ratified the first myelomatosis inhibitor B ortezomib containing alpha-amino boronic 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) Jack H.Lai, William W.Bachovchin, et.al., J.Med.Chem..2007,50,2391-2398.c) George R.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 aminase IV (DPP-4), can be used as the very promising medicine of type ii diabetes, the PT-100 of U.S. Phenomix company wherein, the III phase that has completed FDA is clinical.

Document:

Snow，R.et.al.,J.Am.Chem.Soc.,1994,116,10860-10869.：

Jack?H.Lai,William?W.Bachovchin,et.al.,J.Med.Chem.2007,50,2391-2398.

George?R.Lankas,et.al.,Diabetes,2005,54,2988-2994.

K.Augustyns,P.Van?der?Veken,K.Senten?and?A.Haemers,Current?Medicinal?Chemistry,2005,12,971-998.

Pieter?Van?der?Veken,Achiel?Haemers?and?Koen?Augustyns,Current?Topics?in?Medicinal?Chemistry，2007,7,621-635.

Daniel?J?Drucker,Michael?A?Nauck,Lancet，2006;368:1696–705.

As aminoboronic acid and even the corresponding isomer of corresponding optical purity, aspect chemosynthesis, studying, still there is very large challenge its practicality and diversity aspect, particularly the synthetic aspect of effective, succinct stereoselectivity.Key intermediate with important serine hydrolase inhibitors--dried meat aminoboronic acid synthesize example, the general synthetic method split that reaches of multistep that adopts, mainly with Pinanediol diboron hexahydride ester and pyrroles or Pyrrolidine, it is starting raw material, as document E.Scott Priestley, Carl P.Decicco, US20030008828, (2003,1). report, article one route synthetic method step is long, yield is low, second route stereoselectivity is bad, alkali reagent used is to humidity sensitive, and operability is poor, and reaction formula is as follows:

The method of the asymmetric synthesis of at present relevant alpha-amino boronic acid seldom, in fact only has two kinds of methods to be in the news.A kind of is the Mattheson be widely used in academic and industry member ¹¹method, as document: Donald S.Matteson and Kizhakethil M.Sadhu, J. Am.Chem.SOC.1981, the report of 103,5241-5242., to utilize the Pinanediol diboron hexahydride ester that contains chiral auxiliary to prepare α-chloroboric acid ester, then be further converted to alpha-amino boronic acid, in the method, the side chain of alpha-amino boronic acid is all derivative by alkylboronic acids, this has limited their commercial possibility greatly, and reaction formula is as follows:

The Kettner utilization of Dupont drugmaker is made electrophilic reagent to side chain the method for Matteson is expanded, as document Sharada Jagannathan, Timothy P.Forsyth, and Charles A.Kettner, J.Org.Chem.2001, the report of 66,6375-6380., although enriched to a certain extent the diversity of aminoboronic acid, with regard to it, reagent used and applicable scope still have significant limitation.Reaction formula is as follows:

The above-mentioned method for preparing aminoboronic acid all needs synthesizing through multistep, if directly ideal by the method for a step direct construction target compound, and relevant boron is reported seldom for the addition of the assorted two keys of carbon, document Grace Mann, Kevin D.John, and R.Tom Baker, Org.Lett., 2000,2 (14), 2105-2108.Baker, Deng having reported that a routine N-aryl aromatic aldehyde imines reacts the alpha-amino boronic acid ester that obtains racemization under platinum complex catalysis with Bis (catecholato) diboron (B2cat2), reaction formula is as follows:

On this basis, the method of asymmetric synthesis of directly inducing with the chirality t-butyl sulfonamide, by Ellman, developed successfully, see document Melissa A.Beenen, Chihui An, and Jonathan A.Ellman, J.Am.Chem.Soc..2008, 130, the report of 6910 – 6911, the method utilizes tetramethyl ethylene ketone diboron hexahydride ester to react and obtain chirality alpha-amino boronic acid derivative with chirality tertiary butyl sulfenimide under the catalysis of (ICy) CuOtBu/ sodium tert-butoxide, although it has advantages of highly-solid selectively and higher to aliphatic chain alkyl substituted imine substrate yield, yet still there is the problem of two aspects with regard to current the method, 1) it has used the Cabbeen copper complex of tertiary fourth oxygen copper of NHC as catalyzer, this catalyzer can only prepare and deposit in specific place (as glove box), prospect is used in this industrialization that has limited it, 2) there is limitation in the method for Ellman on the substrate type, usually good (the yield: 74-88%), find the bad (yield: 52-61%), even can not get target product of the yield of arylamino boric acid and test of the yield for alkylamino boric acid,

The core of the method for Ellman is to use the t-butyl sulfonamide substrate boron ester addition reaction carbene catalyzed to Cu (I)-azepine that contains the chiral sulfoxide prothetic group to carry out stereochemistry to induce.Since Wanzlick and Ofele nineteen sixty-eight reported first since azepine Cabbeen (NHC) and metal complex ¹⁵, have successively many stable, separable these compounds ¹⁶be in the news, and this compounds usually obtains good effect when the catalysis organometallic reaction ¹⁷, see a) Herrmann of document, 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.; Nolan, S.P.Eur.J.Inorg.Chem.2005, the report of 1815-1828;

From giving the angle of electronics intensity, the azepine Cabbeen is more similar to rich electrical phosphine compound, 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 stereochemistry character has again obvious difference, sees document: a) Scholl, M.; Trnka, T.M.; Morgan, J.P.; Grubbs, R.H.Tetrahedron Lett.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.Tetrahedron Lett.1999, the report of 40,4787-4790.;

Take σ-key as main with the interaction of metal, the metal/d track to the π retroactive effect of Cabbeen relatively a little less than, be the neutral σ-part of a quasi-representative, see 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, Suzuki-Miyaura, Kumada, Sonogashira, Still, Negishi, in the Buchwald-Harting reaction, be shown in 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.Iht.Ed.2001,40,3387-3389.

Eckhardt,M.,Fu,G.C.,J?Am.Chem.Soc.,2003,125,13642-13643.b)Aitenhoff，G.,Wuertz,S.,Glorius,F.Tetrahedron?Lett.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, first case Cu (I)-azepine Cabbeen (NHC) complex compound { [(NHC) for report ₂cu] [O ₃sCF ₃] ²⁸, 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. report, Buchwald for group copper (I) with now produce the azepine Cabbeen and prepared single NHC and support copper (I) complex compound, proof Cu (I)-azepine Cabbeen (NHC) complex compound is typical two collaborative bodies, and it is along with the increase of substituting group on nitrogen and metal mating capability, and its collaborative power also obviously increases.And it is used in to α, the reduction of the carbon-carbon double bond of beta-unsaturated carbonyl compounds, document: Kang-Sang Lee, Adil, R.Zhugralin and Amir H.Hoveyda, J.Am.Chem.Soc., 2009,131,7253-7255. report, Hoveyda group utilizes azepine Cabbeen catalysis α under metal salt-free exists, and beta-unsaturated carbonyl compounds and the reaction of hypoboric acid ester, build β-boric acid ester carbonyl compound.

Make a general survey of construction process, azepine Cabbeen and the copper complex thereof of aminoboronic acid in the utilization in assorted two key addition reactions to carbon of catalysis diboron hexahydride reagent, up to the present other research groups synthesize the progress in field at aminoboronic acid, the certain vacancy all existed to methodology from the mechanism of reacting and clearly local less than exploring, and the further developing of the synthetic method in this field, to directly promote multifarious such compound library, thereby the research and development of new drug will be had to extremely important effect.

Summary of the invention

The objective of the invention is to disclose a kind of multifarious chiral aminoboronic acid and its preparation method and application, the above-mentioned defect existed to overcome prior art, meet the needs that association area develops.

Multifarious chiral aminoboronic acid of the present invention, for thering is the compound shown in formula I or formula II:

Wherein:

The R representative is containing the straight-chain paraffin base containing 1-12 carbon of the straight-chain paraffin base of 1-12 carbon, the branched alkane alkyl containing 1-12 carbon, the alkylene containing 2-6 carbon, the alkynes that contains 2-6 carbon, aromatic ring yl, aromatic heterocyclic, replacement, the branched alkane alkyl containing 1-12 carbon of replacement, the alkylene containing 2-6 carbon of replacement, alkynes, the aromatic ring yl of replacement or the aromatic heterocyclic of replacement containing 2-6 carbon of replacement;

Preferably, described aromatic ring yl is phenyl, naphthyl or anthryl;

Preferably, described aromatic heterocyclic is pyridyl, pyrimidyl, pyrazinyl, pyrryl, purine radicals or indyl;

The alkylene containing 1-12 carbon of the straight-chain paraffin base containing 1-12 carbon of described replacement, the branched alkane alkyl containing 1-12 carbon of replacement, replacement, alkynes, the aromatic ring yl of replacement or the aromatic heterocyclic of replacement containing 2-6 carbon of replacement, substituting group is hydroxyl, ether, carbonyl, amino, amide group, guanidine radicals, nitro, cyano group or halogen, the preferred chlorine of described halogen;

R ₁=R ₂represent catechu phenolic ester, pinacol ester, dimethylamino ester or (1S, 2S, 3R, 5S)-(+)-2,3-pinine glycol (Pinanediol) ester;

R ₄represent the tertiary butyl, methyl, trifluoromethyl, p-methylphenyl, p-methoxyphenyl or 2,4,6-trimethylphenyl;

R ₅for the cyclic hydrocarbon group of the saturated or unsaturated cycloalkyl group of hydrogen, a 1-8 carbon, nitrogenous or oxygen, containing the straight or branched alkyl of 1-12 carbon, containing the alkylene of 2-6 carbon, contain alkynes base, aromatic ring yl, aromatic heterocyclic or the halogen of 2-6 carbon; Described is chlorine, bromine, iodine or fluorine; Chlorine preferably;

Described aromatic ring yl is replacement or unsubstituted phenyl, naphthyl or anthryl, saturated or unsaturated alkyl, hydroxyl, methoxyl group, trifluoromethyl, amino or halogen that substituting group is 1-4 carbon, and described halogen is fluorine, chlorine or bromine etc.;

Described aromatic heterocyclic is for replacing or unsubstituted pyridyl, pyrimidyl, pyrazinyl, pyrryl, purine radicals, indyl, and saturated or unsaturated alkyl, hydroxyl, methoxyl group, trifluoromethyl, amino or halogen that substituting group is 1-4 carbon, as fluorine, chlorine or bromine etc.;

Preferably, R=R ₅, be the replacement of 1-8 carbon or the saturated or unsaturated aliphatic hydrocarbon of unsubstituted ring-type;

The integer that n is 1～6;

Preferably, R is methyl, propyl group, sec.-propyl, isobutyl-, 3-chloropropyl, adamantyl, 3-to methoxyl group benzyloxy base propyl group, 4-phthalyl amido butyl, phenyl, p-methoxyphenyl, p-methylphenyl, rubigan, benzyl, to benzyloxy benzyl or naphthyl;

Preferably, R=R5, and be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenycyclopropyl or suberyl;

Preferably, described multifarious chiral aminoboronic acid is:

The preparation method of formula I compound of the present invention, comprise the steps:

(1) in organic solvent, under univalent copper ion and the catalysis of azepine carbene precursor, or under alkali and the catalysis of azepine carbene precursor, imine compound I ' and diboron hexahydride reagent are reacted, then from reaction product, collect the formula I compound, temperature of reaction is 15～30 ℃, reaction times is 1-48 hour, preferably 24～48 hours, yield was at 78-93.5%, and optical purity is 98%.Reaction expression is as formula III:

R, R ₁, R ₂, R ₄and R ₅definition the same, R ₃=R _{3 '}=R ₁;

Described univalent copper ion derives from cuprous chloride, cuprous bromide or cuprous iodide;

Described alkali is selected from sodium tert-butoxide, sodium carbonate, salt of wormwood, 1,5-diaza-bicyclo [5,4,0] hendecene-5, cesium carbonate or sodium hydride;

Described organic solvent is selected from tetrahydrofuran (THF), benzene, DMF, ether, methylene dichloride, chloroform or acetonitrile etc.;

Described azepine carbene precursor is the compound with following chemical structure:

Wherein: R ₆the alkoxyl group of the alkyl of 1-6 the carbon that representative does not replace and replaces, 1-6 carbon of replacement, halogen, nitro, amino, replacement or benzene, aromatic ring or the fragrant heterocycle etc. that also encircle;

Preferably hydrogen, 3-fluorine, 3-nitro, 3-methyl, 3-methoxyl group or benzo;

M, Q is nitrogen or carbon;

R ₇represent the carbene alkyl of 1-8 carbon alkyl, 1-8, alkynes base or the aryl of a 1-8 carbon;

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,

Under the catalysis of hydrochloric acid and formic acid, compound L-n and trimethyl orthoformate are reacted, collection type (L-n ') compound from reaction product then, temperature of reaction is 60～100 ℃, and the reaction times is 1-6 hour, and yield is at 89-95%.Reaction expression is as follows:

Compound L-n and with the weight ratio of trimethyl orthoformate be 1:1-20;

The weight of hydrochloric acid is 0.1～150% of compound L-n consumption;

The weight of formic acid is 0.1～150% of compound L-n consumption;

The preparation method of compound L-n comprises the steps:

By the adjacent aryl diamine (1eq) shown in formula (L-m), bromide (1eq), three (dibenzalacetone) two palladiums (Pd2 (dba) ₃) (5%eq) (wherein; the weight content of palladium (Pd) is 21.5%); 2; the two diphenyl phosphines-1 of 2'-; (7.5%eq), sodium tert-butoxide (3eq) and toluene (1ml/mmol, for bromide) are in nitrogen protection for 1'-dinaphthalene (BINAP); 60-110 ℃ of reaction spent the night, and then from reaction product, collects product.Productive rate 70% ~ 90%.Reaction expression suc as formula under:

R ₆, M, Q, Ar ₁define the same;

Described three (dibenzalacetone) two palladiums (Pd2 (dba) ₃) (5%eq) (palladium of reagent (Pd) weight content is 21.5%) refer to palladium (Pd) and (please explain it is what meaning, Luo great Chen) at the part by weight of three (dibenzalacetone) two palladiums

Described three (dibenzalacetone) two palladiums (Pd2 (dba) ₃) adoptable commercial rule of origin.

Described bromide is the fragrant heterocycle that the aromatic ring that replaces of bromine or bromine replace, and on aromatic ring or the aromatic ring or the fragrant heterocycle that replace with substituent bromine on fragrant heterocycle;

Preferably:

The aromatic ring that described bromine replaces is bromobenzene, and full deuterium is for bromobenzene;

The fragrant heterocycle that described bromine replaces is 2-bromopyridine, 3-bromopyridine, 4-bromopyridine, 3-bromo indole or 3-bromo pyrimi piperidine;

The aromatic ring replaced with substituent bromine on aromatic ring is to the methyl bromobenzene, to the methoxyl group bromobenzene, and p-Fluoro bromo benzene, to the nitro bromobenzene or to the cyano group bromobenzene

The fragrant heterocycle replaced with substituent bromine on the virtue heterocycle is 5-trifluoromethyl-2-bromopyridine, 6-methyl-2-bromopyridine, 4-nitrogen, nitrogen dimethyl-2-bromopyridine, 5-trifluoromethyl-3-bromo indole, 5-methyl-3-bromo pyrimi piperidine or 3-methyl-2-bromo-pyrazine;

Described bromide all can adopt commercial product;

Specifically referring to embodiment.

The preparation of described group with imine moiety I ', but reference literature (MaryAnn T.Robak, Melissa A.Herbage, and Jonathan A.Ellman; Chemical Reviews, 2010,110 (6), 3609.) logical method synthetic, all kinds of commercial aldehydes or ketones compounds react gained with (R)-t-butyl sulfonamide.Its reaction expression is:

R wherein, the same identical definition of R5, be all kinds of commercialization aldehydes or ketones.(R)-t-butyl sulfonamide and purity titanium tetraethoxide are commercial prod.

Wherein, the chemical structure of representational group with imine moiety I ' is:

Described diboron hexahydride reagent is the compound had suc as formula shown in B:

Wherein: R ₁, R ₂definition same as above, R ₃=R _{3 '}=R ₁;

But described diboron hexahydride reagent 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 or Sp ²-Sp ³the diboron hexahydride reagent of hydridization; Concrete structure is as follows:

Pinacol ester diboron hexahydride catechu phenolic ester diboron hexahydride Pinanediol ester diboron hexahydride dimethylamino ester diboron hexahydride

Assorted tetramethyl ethylene ketone 2-Isopropylamine alcohol diboron hexahydride (Sp ²-Sp ³the diboron hexahydride reagent of hydridization)

The weight ratio of each component is as follows:

Compound I ': diboron hexahydride reagent=1: 1～3;

Compound I ': univalent copper ion or alkali=1: 0.05～0.2;

Compound I ': azepine carbenes=1: 0.05～0.2;

The preparation method of formula II compound of the present invention, comprise the steps:

In organic solvent, under alkaline matter exists, compound (I ") is carried out to cyclization, then collect from reaction product and obtain the formula II compound; Temperature of reaction is 15～30 ℃, and the reaction times is 1-48 hour, and preferably 24～48 hours, yield was at 78-93.5%, and optical purity is 98%, and reaction expression is as follows:

Wherein:

R ₁, R ₂, R ₄, n definition is the same;

X represents Cl, Br, OSO ₂cF ₃, OSO ₂cH ₃;

The preparation method of compound (I "), be shown in embodiment 5.

Described alkaline matter is selected from sodium tert-butoxide, sodium carbonate, salt of wormwood, 1,5-diaza-bicyclo [5,4,0] hendecene-5, cesium carbonate or sodium hydride;

Described organic solvent is tetrahydrofuran (THF), benzene, DMF, ether, methylene dichloride, chloroform or acetonitrile etc.;

The weight ratio of each component is as follows:

Compound (I "): alkaline matter=1: 1～3, preferably 1～2;

Multifarious chiral aminoboronic acid of the present invention, can be for the preparation of the various medicine (tumours with critical treatment effect, type-II diabetes, the third liver, virus etc.), the compound 4 be specifically related to as prepared with the present invention can be used for preparing myelomatosis inhibitor B ortezomib, and the preparation method is shown in document Melissa A.Beenen as follows, Chihui An, and Jonathan A.Ellman, J.Am.Chem.Soc.2008, the report of 130,6910 – 6911, as the Compound C-3 prepared with the present invention, by with conventional deprotection method (reacting in the methanol solution of 4N hydrogenchloride), slough tertiary butyl sulfinyl, form the hydrochloride of dried meat aminoboronic acid ester, can be used for preparing the PT-100 of the U.S. Phenomix company of introduction part, it is very effective DPP-4 inhibitor, can be used as the very promising medicine of type ii diabetes, the III phase that has completed FDA is clinical, preparation method's reference literature is Snow a), R.et.al., J.Am.Chem.Soc., 1994, 116, 10860-10869.b) Jack H.Lai, William W.Bachovchin, et.al., J.Med.Chem.2007, 50, 2391-2398.c) George R.Lankas, et.al., Diabetes, 2005, 54, 2988-2994. report.

Beneficial effect of the present invention is: described multifarious chiral aminoboronic acid, and wherein by the present invention, preparing related chemical compound lot is that at present can't prepare by other synthetic methods, for new drug research provides abundant the type compound library; The compound 4 prepared by this law and Compound C 3, can improve yield and stereoselectivity, can reduce the preparation cost of this 2 class medicine and simplify synthetic route.The economic benefit had.

Embodiment

The addition representativeness synthetic method of boric acid ester to tertiary butyl sulfenimide:

Logical method 1(has cuprous chloride to participate in):

Reaction, among nitrogen protection, first adds 0.2mmol ligand L-01 ' (0.1eq.), 0.2mmol cuprous chloride (0.1eq.), and 0.2mmol sodium tert-butoxide (0.1eq.) and solvent benzol (10ml), at room temperature stir 4hr;

Reaction solution by colourless become green to light/dark balance.Afterwards, 2mmol tertiary butyl sulfenimide (1eq.) is dissolved in benzene (5ml), 2mmol boric acid ester (1eq.) is dissolved in benzene (5ml), be added in reaction tubes.Afterwards, room temperature reaction 48hr.By TLC monitoring reaction process.Reaction adds EA(30ml after finishing) dilution, and use K ₂cO ₃the washing organic layer.Use afterwards EA(2 * 30ml) aqueous layer extracted.Merge organic layer Na ₂sO ₄drying, filter concentrating under reduced pressure.Product is with inactivation silica gel (water inactivation) through the row column chromatography for separation, and developping agent is used the chloroform/methanol system.

Logical method 2(participates in without cuprous chloride):

Reaction, among nitrogen protection, first adds 0.2mmol azepine carbene precursor L-01 ' (0.1eq.), and 0.2mmol cesium carbonate (0.1eq.) and solvent benzol (10ml), at room temperature stir 4hr.Reaction solution by colourless become green to light/dark balance.Afterwards, 2mmol tertiary butyl sulfenimide (1eq.) is dissolved in benzene (5ml), 2mmol boric acid ester (1eq.) is dissolved in benzene (5ml), be added in reaction tubes.Afterwards, room temperature reaction 48hr.By TLC monitoring reaction process.Reaction adds EA(30ml after finishing) dilution, and use K ₂cO ₃the washing organic layer.Use afterwards EA(2 * 30ml) aqueous layer extracted.Merge organic layer Na ₂sO ₄drying, filter concentrating under reduced pressure.Product is with inactivation silica gel (water inactivation) through the row column chromatography for separation, and developping agent is used the chloroform/methanol system.

Azepine carbene precursor L-01's ' is synthetic:

The 1st step: compound L-01 synthetic:

O-Phenylene Diamine (2.162g, 20mmol), bromobenzene (6.281g, 40mmol), Pd ₂(dba) ₃(0.916g, 1mmol) (the Pd content of reagent is 21.5%), the two diphenyl phosphines-1 of 2,2'-; 1'-dinaphthalene (BINAP), (0.934g, 7.5%eq); sodium tert-butoxide (5.766g, 3eq) and dry toluene (20ml) add in the reaction tubes of nitrogen protection, 110 ℃ of temperature.Reaction is spent the night.After reaction, liquid is gone out solid with filter paper, and by ethyl acetate, solid is washed, and gained liquid merges, is spin-dried for, and crossing post, to take product be pale solid 4.478g, productive rate 86%.

¹H-NMR(CDCl ₃,δ,ppm):7.33-7.29(m,6H),7.01-6.91(m,8H),5.65(s,2H,NH). ¹³C-NMR(CDCl ₃,δ,ppm):145.0,135.0,129.4,122.5,120.4,119.5,116.7.

The 2nd step: compound L-01 ' synthetic:

Upper step product 2.11g(8mmol) add in the 16ml trimethyl orthoformate, splash into the concentrated hydrochloric acid that the 0.8ml weight concentration is 36%, and 2 formic acid.Be heated to 80 degree, react 2 hours.TLC follows the tracks of raw material and disappears.Reaction solution is spin-dried for.With chloroform/normal hexane recrystallization.Productive rate 90%.White solid 2.21g.

¹H-NMR(DMSO,δ,ppm):10.64(s,1H),7.98-7.95(m,6H),7.83-7.74(m,8H). ¹³C-NMR(DMSO,δ,ppm):143.3,133.5,131.7,131.2,130.9,128.3,125.9,114.3.

Embodiment 1

The preparation of aminoboronic acid ester and sign:

Compound (1). adopt logical method 1 to be reacted.

Add 295mg(2mmol) tertiary butyl sulfenimide Compound1 ', react 48 hours.

The silica gel that reaction mixture is crossed by the water inactivation is through the row column chromatography purification, and developping agent is the chloroform/methanol system.Products therefrom is that proterties is light yellow oil (253mg, yield:85%) at ambient temperature.

¹H-NMR(DMSO,δ,ppm):4.78(d,j=6.4,0.43H,NH),4.34(dd,j ₁=1.6Hz,j ₂=8.8Hz,1H),2.93(m,1H,CHN),2.30(m,1H),2.17(m,1H),1.97(m,1H),1.87(m,1H),1.73(m,1H),1.32(s,3H),1.26(s,3H),1.20(d,j=7.2Hz,3H),1.12(m,1H),1.09(s,9H),0.82(s,3H). ¹³C-NMR(DMSO,δ,ppm):85.9,77.5,55.5,51.3,38.3,35.4,28.8,27.3,26.3,24.1,23.1,19.2,19.1.

Embodiment 2

Adopt logical method 2 to be reacted.

Add 351mg(2mmol) tertiary butyl sulfenimide Compound2 ', react 48 hours.

The silica gel that reaction mixture is crossed by the water inactivation is through the row column chromatography purification, and developping agent is the chloroform/methanol system.Products therefrom is that proterties is faint yellow oily matter (322mg, yield:92%) at ambient temperature.

¹H-NMR(DMSO,δ,ppm):4.76(d,j=6.8Hz,1H,NH),4.34(dd,j ₁=2Hz,j ₂=8.8Hz,1H),2.82(m,1H,CHN),2.30(m,1H),2.16(m,1H),1.97(m,1H),1.87(m,1H),1.71(m,1H),1.56(m,2H),1.34(m,2H),1.32(s,3H),1.25(s,3H),1.13(m,1H),1.08(s,9H),0.87(t,j=7.2Hz,3H),0.82(s,3H). ¹³C-NMR(DMSO,δ,ppm):85.9,77.4,55.7,51.2,38.3,35.5,35.5,28.8,27.3,26.4,24.1,23.1,20.1,14.5.

Embodiment 3

Adopt logical method 1 to be reacted.

Add 351mg(2mmol) imines Compound3 ', react 48 hours.The silica gel that reaction mixture is crossed by the water inactivation is through the row column chromatography purification, and developping agent is the chloroform/methanol system.Products therefrom is that proterties is faint yellow oily matter (308mg, yield:88%) at ambient temperature.

¹H-NMR(DMSO,δ,ppm):4.73(d,j=6.8Hz,1H,NH),4.34(m,1H),2.66(t,j=6.4Hz,1H,CHN),2.32(m,1H),2.16(m,1H),1.98(m,1H),1.87(m,2H),1.70(m,1H),1.32(s,3H),1.25(s,3H),1.18(m,1H),1.09(s,9H),0.92(d,j=7.2Hz,6H),0.82(s,3H). ¹³C-NMR(DMSO,δ,ppm):77.4,55.9,51.2,38.3,35.5,31.2,28.9,27.3,26.5,24.2,23.0,20.8,20.0.

Embodiment 4

Adopt logical method 1 to be reacted.

Add 379mg(2mmol) imines Compound4 ', react 48 hours.The silica gel that reaction mixture is crossed by the water inactivation is through the row column chromatography purification, and developping agent is the chloroform/methanol system.Products therefrom is that proterties is colorless oil (341mg, yield:90%) at ambient temperature.

¹H-NMR(CDCl ₃,δ,ppm):4.33(dd,j ₁=2Hz,j ₂=8.8Hz,1H),3.52(s,br,1H,NH),3.15(m,1H,CHN),3.10(m,1H),2.35(m,1H),2.23(m,1H),2.07(m,1H),1.93(m,1H),1.87(m,1H),1.76(m,1H),1.60(m,1H),1.41(s,3H),1.31(s,3H),1.21(s,9H),1.17(m,1H),0.95(dd,j ₁=1.2Hz,j ₂=6.4Hz,6H),0.86(s,3H). ¹³C-NMR(CDCl ₃,δ,ppm):86.2,78.2,56.0,51.2,42.8,39.5,38.2,35.4,28.5,27.0,26.4,25.6,24.0,22.7,22.6,22.5.

Embodiment 5

Adopt logical method 1 to be reacted.

Add 420mg(2mmol) imines Compound5 ', react 48 hours.The silica gel that reaction mixture is crossed by the water inactivation is through the row column chromatography purification, and developping agent is the chloroform/methanol system.Products therefrom is that proterties is faint yellow oily matter (373mg, yield:89%) at ambient temperature.

¹H-NMR(DMSO,δ,ppm):4.90(d,j=6.4Hz,0.4H,NH),4.36(dd,j ₁=2Hz,j ₂=6.8Hz,1H),3.63(t,j=6.4Hz,2H),2.85(t,j=7.2Hz,1H,CHN),2.32(m,1H),2.17(m,1H),1.98(t,j=5.6Hz,1H),1.88(m,1H),1.81(m,2H),1.72(m,2H),1.70(m,1H),1.33(s,3H),1.26(s,3H),1.13(m,1H),1.09(s,9H),0.82(s,3H). ¹³C-NMR(DMSO,δ,ppm):86.0,77.5,55.8,51.2,45.9,38.3,35.4,30.6,30.5,30.1,28.8,27.3,26.4,24.1,23.1.

Embodiment 6

Adopt logical method 1 to be reacted.

Add 535mg(2mmol) imines Compound6 ', react 48 hours.The silica gel that reaction mixture is crossed by the water inactivation is through the row column chromatography purification, and developping agent is the chloroform/methanol system.Products therefrom is that proterties is faint yellow oily matter (455mg, yield:85%) at ambient temperature.

¹H-NMR(DMSO,δ,ppm):4.38(m,1H,NH),4.36(m,1H),2.46(d,j=8.4Hz,1H,CHN),2.33(m,1H),2.18(m,1H),1.99(t,j=5.6Hz,1H),1.94(m,3H),1.88(m,1H),1.69(m,7H),1.57(m,3H),1.49(m,3H),1.33(s,3H),1.26(s,3H),1.18(m,1H),1.09(s,9H),0.82(s,3H). ¹³C-NMR(DMSO,δ,ppm):86.0,77.3,56.2,51.2,38.3,37.1,35.7,35.6,28.9,28.4,27.3,26.6,24.2,23.0.

Embodiment 7

Adopt universal method 1 reaction.

Add 623mg(2mmol) imines Compound7 ', react 48 hours.The silica gel that reaction mixture is crossed by the water inactivation is through the row column chromatography purification, and developping agent is the chloroform/methanol system.Products therefrom is that proterties is faint yellow oily matter (542mg, yield:87%) at ambient temperature.

¹H-NMR(DMSO,δ,ppm):7.23(d,j＝8.4Hz,2H),6.90(m,2H),4.78(m,0.5H,NH),4.36(s,2H),4.33(dd,j ₁=1.6Hz,j ₂=7.2Hz,1H),3.74(s,3H),3.38(m,2H),2.83(m,1H,CHN),2.30(m,1H),2.15(m,1H),1.98(m,1H),1.86(m,1H),1.72(m,1H),1.64(m,4H),1.31(s,3H),1.25(s,3H),1.15(m,1H),1.08(s,9H),0.81(s,3H). ¹³C-NMR(DMSO,δ,ppm):159.1,131.0,129.5,114.0,85.9,77.5,71.9,69.7,55.7,55.5,51.2,38.4,38.3,36.0,35.5,30.0,30.0,28.9,28.8,27.4,27.3,27.1,26.4,24.1,23.1.

Embodiment 8

Adopt universal method 1 reaction.

Add 669mg(2mmol) imines Compound8 ', react 48 hours.The silica gel that reaction mixture is crossed by the water inactivation is through the row column chromatography purification, and developping agent is the chloroform/methanol system.Products therefrom is that proterties is faint yellow oily matter (609mg, yield:91%) at ambient temperature. ¹H-NMR(DMSO,δ,ppm):7.86(m,4H),4.74(d,j=6.4Hz,1H,NH),4.21(m,1H),3.57(t,j=6.8Hz,2H),2.78(m,1H,CHN),2.22(m,1H),2.00(,1H),1.86(m,1H),1.69(m,1H),1.58(m,5H),1.30(m,2H),1.22(s,3H),1.19(s,3H),1.06(s,9H),1.03(m,1H),0.78(s,3H). ¹³C-NMR(DMSO,δ,ppm):168.4,134.8,132.1,123.4,85.9,77.4,55.6,51.1,38.2,37.9,35.4,32.7,28.7,28.3,27.3,26.4,24.1,23.0.

Embodiment 9

Adopt logical method 1 to be reacted.

Add 418mg(2mmol) imines Compound9 ', react 48 hours.The silica gel that reaction mixture is crossed by the water inactivation is through the row column chromatography purification, and developping agent is the chloroform/methanol system.Products therefrom is that proterties is faint yellow oily matter (368mg, yield:88%) at ambient temperature.

¹H-NMR(DMSO,δ,ppm):7.28(m,4H),7.18(m,1H),5.47(d,j=5.6Hz,0.44H,NH),4.34(m,1H),4.13(d,j＝5.6Hz,1H,CHN),2.29(m,1H),2.02(m,1H),1.93(m,1H),1.78(m,1H),1.59(m,1H),1.26(s,3H),1.21(s,3H),1.13(s,9H),0.86(m,1H),0.78(s,3H). ¹³C-NMR(DMSO,δ,ppm):141.7,128.6,127.7,126.8,86.2,77.7,56.2,51.2,38.3,35.3,28.6,27.2,26.0,24.1,23.1.

Embodiment 10

Adopt universal method 1 reaction.

Add 479mg(2mmol) imines Compound10 ', react 48 hours.The silica gel that reaction mixture is crossed by the water inactivation is through the row column chromatography purification, and developping agent is the chloroform/methanol system.Products therefrom is that proterties is faint yellow oily matter (436mg, yield:91%) at ambient temperature.

¹H-NMR(DMSO,δ,ppm):7.26(d,j=8.8Hz,2H),6.86(d,j=8.8Hz,2H),5.30(d,j=4.2Hz,0.53H,NH),4.33(m,1H),4.05(d,j＝5.6Hz,1H,CHN),3.73(s,3H),2.28(m,1H),2.04(m,1H),1.94(m,1H),1.81(m,1H),1.63(m,1H),1.25(s,3H),1.20(s,3H),1.12(s,9H),0.89(m,1H),0.79(s,3H). ¹³C-NMR(DMSO,δ,ppm):158.4,133.3,129.1,114.0,86.2,77.6,56.1,55.5,51.2,38.3,35.4,28.7,27.2,26.1,24.1,23.1.

Embodiment 11

Adopt universal method 1 reaction.

Add 447mg(2mmol) imines Compound11 ', react 48 hours.The silica gel that reaction mixture is crossed by the water inactivation is through the row column chromatography purification, and developping agent is the chloroform/methanol system.Products therefrom is that proterties is faint yellow oily matter (402mg, yield:90%) at ambient temperature.

¹H-NMR(DMSO,δ,ppm):7.23(d,j=8Hz,2H),7.10(d,j=7.6Hz,2H),5.34(d,j=5.6Hz,1H,NH),4.33(dd,j ₁=1.6Hz,j ₂=8.8Hz,1H),4.07(d,j=6Hz,1H,CHN),2.27(m,1H),2.27(s,3H),2.03(m,1H),1.93(m,1H),1.79(m,1H),1.64(m,1H),1.25(s,3H),1.21(s,3H),1.12(s,9H),0.89(m,1H),0.79(s,3H). ¹³C-NMR(DMSO,δ,ppm):138.6,135.8,129.2,127.8,86.2,77.7,56.1,51.3,38.3,35.4,28.7,27.2,26.1,24.1,23.1,21.1.

Embodiment 12

Adopt universal method 1 reaction.

Add 488mg(2mmol) imines Compound12 ', react 48 hours.The silica gel that reaction mixture is crossed by the water inactivation is through the row column chromatography purification, and developping agent is the chloroform/methanol system.Products therefrom is that proterties is faint yellow oily matter (405mg, yield:83%) at ambient temperature.

¹H-NMR(DMSO,δ,ppm):7.38(m,4H),4.23(m,1H),4.17(m,1H,NH),4.17(m,1H,CHN),2.28(m,1H),2.18(m,1H),1.93(m,1H),1.86(m,1H),1.70(m,1H),1.30(s,3H),1.25(s,3H),1.14(s,9H),1.13(m,1H),0.81(s,3H). ¹³C-NMR(DMSO,δ,ppm):139.5,131.9,130.0,128.6,83.4,76.1,55.7,51.8,47.7,38.4,36.0,29.0,27.4,26.4,24.1,23.1.

Embodiment 13

Adopt universal method 1 reaction.

Add 447mg(2mmol) imines Compound13 ', react 48 hours.The silica gel that reaction mixture is crossed by the water inactivation is through the row column chromatography purification, and developping agent is the chloroform/methanol system.Products therefrom is that proterties is faint yellow oily matter (398mg, yield:89%) at ambient temperature.

¹H-NMR(DMSO,δ,ppm):7.24(m,5H),4.88(d,j=6Hz,1H,NH),4.23(m,1H),3.12(m,1H,CHN),2.96(m,1H),2.85(m,1H),2.25(m,1H),1.93(m,1H),1.88(m,1H),1.78(m,1H),1.64(m,1H),1.24(s,3H),1.21(s,3H),1.08(s,9H),0.80(m,1H),0.77(s,3H). ¹³C-NMR(DMSO,δ,ppm):139.2,129.6,128.6,126.7,86.0,77.5,55.7,51.1,38.2,35.2,28.6,27.3,26.1,24.1,23.0.

Embodiment 14

Adopt universal method 1 reaction.

Add 519mg(2mmol) imines Compound15 ', react 48 hours.The silica gel that reaction mixture is crossed by the water inactivation is through the row column chromatography purification, and developping agent is the chloroform/methanol system.Products therefrom is that proterties is faint yellow oily matter (441mg, yield:85%) at ambient temperature.

¹H-NMR(DMSO,δ,ppm):7.88(m,4H),7.51(m,3H),4.32(d,j=8.4Hz,1H,NH),4.32(m,1H),4.22(d,j=8.4Hz,1H,CHN),2.28(m,1H),2.18(m,1H),1.93(m,1H),1.87(m,1H),1.67(m,1H),1.30(s,3H),1.25(s,3H),1.17(s,9H),1.13(m,1H),0.81(s,3H). ¹³C-NMR(DMSO,δ,ppm):138.0,133.3,132.7,128.2,128.0,128.0,126.8,126.6,126.5,126.2,83.3,76.1,55.7,51.8,48.7,48.5,38.4,36.0,29.0,27.4,26.4,24.1,23.2.

Embodiment 15

Adopt universal method 1 reaction.

Add 447mg(2mmol) imines Compound18 ', react 48 hours.The silica gel that reaction mixture is crossed by the water inactivation is through the row column chromatography purification, and developping agent is the chloroform/methanol system.Products therefrom is that proterties is faint yellow oily matter (250mg, yield:56%) at ambient temperature.

¹H-NMR(DMSO,δ,ppm):7.42(m,2H),7.30(m,2H),7.17(m,1H),5.17(s,0.5H,NH),4.33(m,1H),2.28(m,1H),2.05(m,1H),1.92(m,1H),1.78(m,1H),1.67(s,3H),1.53(m,1H),1.21(s,3H),1.19(s,9H),1.13(s,3H),0.89(m,1H),0.77(s,3H). ¹³C-NMR(DMSO,δ,ppm):146.2,128.3,128.2,127.2,126.5,126.4,86.4,77.8,56.6,51.3,38.4,35.4,31.2,28.6,27.2,26.6,26.2,24.1,23.3,23.1.

Embodiment 16

Adopt universal method 1 reaction.

Add 402mg(2mmol) imines Compound18 ', react 48 hours.The silica gel that reaction mixture is crossed by the water inactivation is through the row column chromatography purification, and developping agent is the chloroform/methanol system.Products therefrom is that proterties is faint yellow oily matter (488mg, yield:64%) at ambient temperature.

¹H-NMR(DMSO,δ,ppm):4.48(s,1H,NH),4.35(m,1H),2.87(m,1H,CHN),2.20(m,1H),2.05(m,2H),1.91(m,2H),1.68(m,4H),1.50(m,1H),1.36(s,3H),1.28(m,7H),1.12(s,3H),1.09(s,9H),0.82(s,3H). ¹³C-NMR(DMSO,δ,ppm):86.0,77.5,55.8,51.2,45.9,38.3,35.4,30.6,30.5,30.1,28.8,27.3,26.4,24.1,23.1.

Embodiment 17

Under different ligands catalysis, boric acid ester is to the representative synthetic method of the addition of tertiary butyl sulfenimide.

1) selected respectively ligand L-01, L-02, L-03, L-06 to being reacted under representative synthetic method (method 1) reaction conditions of the addition of tertiary butyl sulfenimide, be take the butyraldehyde-n imines as substrate according to boric acid ester, and result is not found target product.

2) selected respectively ligand L-020 ', L-021 ', L-022 ' is reacted under addition representativeness synthetic method (method 1) reaction conditions to tertiary butyl sulfenimide according to boric acid ester, take the butyraldehyde-n imines as substrate, found that: the yield of target product is respectively 91%, 35%, and 42%.

The preparation method of compound (I "): adopt the general method of above method 1 synthetic.

Embodiment 18

The representative synthetic method of the cyclisation of the aminoboronic acid ester that the end halogen replaces.

Reaction is among nitrogen protection.The aminoboronic acid ester that adds 2mmol end halogen to replace, 2.1mmol sodium tert-butoxide (1.05eq.) and solvent DMF (10ml), at room temperature stir 6hr.By TLC monitoring reaction process.Reaction adds EA(30ml after finishing) and water (30ml).With EA(2 * 30ml) aqueous layer extracted.Merge organic layer Na ₂sO ₄drying, filter concentrating under reduced pressure.Product is with inactivation silica gel (water inactivation) through the row column chromatography for separation, and developping agent is used the chloroform/methanol system.

The structure of the aminoboronic acid ester that the end halogen replaces is as follows:

Embodiment 19

The universal method of the aminoboronic acid ester that employing replaces the end halogen is through the row reaction.Add 780mg(2mmol) imines Compound5, react 6 hours.The silica gel that reaction mixture is crossed by the water inactivation is through the row column chromatography purification, and developping agent is the chloroform/methanol system.Products therefrom is that proterties is faint yellow oily matter (586mg, yield:83%) at ambient temperature.

¹H-NMR(DMSO,δ,ppm):4.36(dd,j ₁=2Hz,j ₂=6.8Hz,1H),3.63(t,j=6.4Hz,2H),2.85(t,j=7.2Hz,1H),2.32(m,1H),2.17(m,1H),1.98(t,j=5.6Hz,1H),1.88(m,1H),1.81(m,2H),1.72(m,2H),1.70(m,1H),1.33(s,3H),1.26(s,3H),1.13(m,1H),1.09(s,9H),0.82(s,3H). ¹³C-NMR(DMSO,δ,ppm):86.0,77.5,55.8,51.2,45.9,38.3,35.4,30.6,30.5,30.1,28.8,27.3,26.4,24.1,23.1。

Claims

1. multifarious chiral aminoboronic acid, is characterized in that, for thering is the compound shown in formula I or formula II:

Wherein:

Described is the straight-chain paraffin base containing 1-12 carbon replaced, the branched alkane alkyl containing 1-12 carbon of replacement, the alkylene containing 1-12 carbon of replacement, alkynes, the aromatic ring yl of replacement or the aromatic heterocyclic of replacement containing 2-6 carbon of replacement, and substituting group is hydroxyl, ether, carbonyl, amino, amide group, guanidine radicals, nitro, cyano group or halogen;

R ₁=R ₂, represent catechu phenolic ester, pinacol ester, dimethylamino ester or (1S, 2S, 3R, 5S)-(+)-2,3-pinine glycol (Pinanediol) ester;

The integer that n is 1～6.

2. multifarious chiral aminoboronic acid according to claim 1, is characterized in that, the aromatic ring yl of R representative is phenyl, naphthyl or anthryl; The aromatic heterocyclic of R representative is pyridyl, pyrimidyl, pyrazinyl, pyrryl, purine radicals or indyl.

3. multifarious chiral aminoboronic acid according to claim 1, is characterized in that R=R ₅, be the replacement of 1-8 carbon or the saturated or unsaturated aliphatic hydrocarbon of unsubstituted ring-type.

4. multifarious chiral aminoboronic acid according to claim 3, is characterized in that, R=R5, and be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, phenycyclopropyl or suberyl.

5. according to the described multifarious chiral aminoboronic acid of claim 1～4 any one, it is characterized in that, R is methyl, propyl group, sec.-propyl, isobutyl-, 3-chloropropyl, adamantyl, 3-to methoxyl group benzyloxy base propyl group, 4-phthalyl amido butyl, phenyl, p-methoxyphenyl, p-methylphenyl, rubigan, benzyl, to benzyloxy benzyl or naphthyl.

6. according to the described multifarious chiral aminoboronic acid of claim 1～4 any one, it is characterized in that R ₅the aromatic ring yl of representative is replacement or unsubstituted phenyl, replacement or unsubstituting naphthyl or replacement or does not replace anthryl, saturated or unsaturated alkyl, hydroxyl, methoxyl group, trifluoromethyl, amino or halogen that substituting group is 1-4 carbon, and described halogen is fluorine, chlorine or bromine;

R ₅the described aromatic heterocyclic of representative is for replacing or unsubstituted pyridyl, replacement or not substituted pyrimidyl, replacement or do not replace pyrazinyl, replacement or not substituted azole base, replacement or not substituted purinyl, replacement or not substituted indolyl, saturated or unsaturated alkyl, hydroxyl, methoxyl group, trifluoromethyl, amino or halogen that substituting group is 1-4 carbon.

7. multifarious chiral aminoboronic acid according to claim 5, is characterized in that R ₅the aromatic ring yl of representative is replacement or unsubstituted phenyl, replacement or unsubstituting naphthyl or replacement or does not replace anthryl, saturated or unsaturated alkyl, hydroxyl, methoxyl group, trifluoromethyl, amino or halogen that substituting group is 1-4 carbon, and described halogen is fluorine, chlorine or bromine;

8. multifarious chiral aminoboronic acid, is characterized in that, for:

9. according to the preparation method of the described formula I compound of claim 1～8 any one, it is characterized in that, comprise the steps:

(1) in organic solvent, under univalent copper ion and the catalysis of azepine carbene precursor, or, under alkali and the catalysis of azepine carbene precursor, imine compound I ' and diboron hexahydride reagent are reacted, then from reaction product, are collected the formula I compound.Reaction expression is as formula III:

R, R ₁, R ₂, R ₄and R ₅definition described with claim 1, R ₃=R _{3 '}=R ₁.

10. method according to claim 9, is characterized in that, described univalent copper ion derives from cuprous chloride, cuprous bromide or cuprous iodide;

Wherein: R ₆the alkoxyl group of the alkyl of 1-6 the carbon that representative does not replace and replaces, 1-6 carbon of replacement, halogen, nitro, amino, replacement or the benzene, aromatic ring or the fragrant heterocycle that also encircle;

M, Q is nitrogen or carbon;

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.

11. method according to claim 10, is characterized in that, R ₆for hydrogen, 3-fluorine, 3-nitro, 3-methyl, 3-methoxyl group or benzo.

12. method according to claim 10, is characterized in that, the azepine carbene precursor is:

The chemical structure of described group with imine moiety I ' is:

Wherein: R ₁, R ₂definition is with claim 1, R ₃=R _{3 '}=R ₁.

13. method according to claim 12, is characterized in that, described diboron hexahydride reagent is selected from catechu phenolic ester, pinacol ester, dimethylamino ester, (1S, 2S, 3R, 5S)-(+)-2,3-pinine glycol (Pinanediol) ester or Sp ²-Sp ³the diboron hexahydride reagent of hydridization.

14. the preparation method according to the described formula II compound of claim 1～8 any one, is characterized in that, comprises the steps:

In organic solvent, under alkaline matter exists, compound (I ") is carried out to cyclization, then collect from reaction product and obtain the formula II compound; Reaction expression is as follows:

Wherein:

R ₁, R ₂, R ₄, n definition is described with claim 1;

X represents Cl, Br, OSO ₂cF ₃, OSO ₂cH ₃.

15. method according to claim 14, is characterized in that, described alkaline matter is selected from sodium tert-butoxide, sodium carbonate, salt of wormwood, 1,5-diaza-bicyclo [5,4,0] hendecene-5, cesium carbonate or sodium hydride.

16. the application according to the described multifarious chiral aminoboronic acid of claim 1～8 any one, is characterized in that, for the preparation for the treatment of tumour, type-II diabetes, the third liver or virus disease medicine.