CN103408572B - Chiral aminoboronic acid derivative and its preparation method and application - Google Patents

Abstract

The invention belongs to the field of organic chemistry, relates to a derivative of chiral aminoboronic acid and its preparation method and application, and discloses a chiral aminoboronic acid derivative with a structure of general formula (I). Reagent, synthesized with azacarbene ligand and base as catalyst. The boronic acid derivatives can be used to prepare drugs for treating tumors or diabetes, and can also be used as intermediates to prepare other drugs. The synthesis method of the invention can improve the yield and stereoselectivity, reduce the cost of medicine preparation, simplify the synthesis route, and have better economic benefits.

Description

Chiral aminoboronic acid derivative and its preparation method and application

technical field

The invention belongs to the field of organic synthesis, and relates to chiral aminoboronic acid and its preparation method and application.

Background technique

In nature, although there are no natural aminoboronic acid compounds, the boronic acid group has a very special pseudo-decoration of natural aminocarboxylic acid, so that it has fascinating biological activity, which is similar to the characteristics of natural amino acids The aminoboronic acid compound is a compound with the following structure:

Wherein: R is various substituents characteristic of natural amino acids.

In recent years, aminoboronic acid, as the key pharmacophore of serinase antagonism, has attracted more and more attention in drug design. Due to the unique physical and chemical properties and spatial structure of boron atoms (with empty p orbitals and small atomic radius), Aminoboronic acid can be designed as a variety of important hydrolase inhibitors. For example, the literature Shenvi, al., US4499082 (1985) Shenvi, etc. revealed that peptidylaminoboronic acid TM-1 compounds can be used as inhibitors of proteolytic enzymes, the literature Kentter, Shenvi, al., US5187157 (1993), US5242904 (1993), US5250720 (1993) Kentter, Shenvi revealed that peptidylaminoboronic acid TM-1 compounds can also be used as reversible inhibitors of insulin-like serine hydrolase, which can act on thrombin, plasma kallikrein, and plasmin, literature Kleeman, al., US5169841 (1992). Kleeman reveals that N-terminal peptidyl-linked aminoboronic acid TM-2 compounds have the activity of inhibiting renin, Kettner, al., WO200102424 (2001) Kettner, etc. disclose peptidyl aminoboronic acid TM -3 compounds have the effect of inhibiting hepatitis C virus, Kinder, al., US5106948 (1992) Kinder etc. reported that the aminoboronic acid TM-2 compound of N-terminal linking peptide group has the effect of inhibiting tumor cell growth, same Bachovchin, al., WO20070005991 (2007) Bachovchin et al. revealed that peptidylaminoboronic acid TM-4 compounds have the effect of inhibiting fibroblast activation protein (FPA), which indicates that this type of compound has anti-tumor activity. Later related studies showed that Has the potential to inhibit pancreatic cancer, Fleming; PaulE.al., WO2011123502 (2011) Fleming and PaulE. et al. revealed that cyclopropyl-containing aminoboronic acid TM-5 compounds have the effect of inhibiting tumor cell growth, FDA recently approved the first Examples include Bortezomib, a myeloma inhibitor of aminoboronic acid, has been used clinically. In addition, literature a) Snow, 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 proline boronic acid of peptidyl is dipeptidyl prolinase IV (DPP- 4) is a very effective inhibitor, which can be used as a promising drug for the treatment of type II diabetes. Among them, PT-100 of the American Phenomix company has completed the Phase III clinical trial of the FDA.

literature:

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. Vander Veken, K. Senten and A. Haemers, Current Medicinal Chemistry, 2005, 12, 971-998.

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

Daniel JDrucker, Michael ANauck, Lancet, 2006;368:1696–705.

As aminoboronic acids and even corresponding optically pure enantiomers are studied in chemical synthesis, there are still great challenges in terms of practicability and diversity, especially in terms of efficient and concise stereoselective synthesis. Taking the synthesis of proline boronic acid, the key intermediate of an important serine hydrolase inhibitor, as an example, a multi-step synthesis and resolution method is generally used, mostly using Pinanediol diborane ester and pyrrole or tetrahydropyrrole as starting materials , as the report of document E.ScottPriestley, CarlP.Decicco, US20030008828, (2003, 1). The first route synthetic method step is long, and yield is low, and the second route stereoselectivity is not good, and the alkali reagent used is to humidity Sensitive and poor operability, the reaction formula is as follows:

At present, there are few methods for the asymmetric synthesis of aminoboronic acid, and actually only two methods have been reported. One is the method of Mattheson who is widely used in academia and industry, as reported in the literature: DonaldS.MattesonandKizhakethilM.Sadhu, J.Am.Chem.SOC.1981,103,5241-5242. The pinanediol diborane ester of base is prepared chloroborate, and then further converted into aminoboronic acid, in this method, the side chains of aminoboronic acid are all derived from alkylboronic acid, which greatly limits the possibility of their commercialization. The formula is as follows:

Kettner of Dupont Pharmaceuticals has extended Matteson's method by making the side chain an electrophile, as reported by SharadaJagannathan, TimothyP.Forsyth, and CharlesA.Kettner, J.Org.Chem.2001, 66, 6375-6380. , although it has enriched the diversity of aminoboronic acids to a certain extent, it still has great limitations in terms of the reagents used and the scope of application. The reaction formula is as follows:

The above-mentioned methods for preparing aminoboronic acid all need to be synthesized in multiple steps. If the method of directly constructing the target compound directly by one step is the most ideal, there are few reports on the addition of boron to the carbon-hetero double bond. Documents GraceMann, KevinD.John, andR .TomBaker, Org.Lett., 2000, 2(14), 2105-2108.Baker et al. reported a case of N-aryl aromatic aldimine with Bis(catecholato)diboron(B ₂ cat ₂ ) reaction to obtain racemic amino borate, the reaction formula is as follows:

On this basis, the direct asymmetric synthesis method induced by chiral tert-butylsulfinamide was successfully developed by Ellman, see literature MelissaA.Beenen, ChihuiAn, and JonathanA.Ellman, J.Am.Chem.Soc.2008, 130, 6910–6911 reported that the method utilizes pinacol diborane ester to react with chiral tert-butylsulfinimide under the catalysis of (ICy)CuOtBu/sodium tert-butoxide to obtain chiral Aminoboronic acid derivatives, although it has the advantages of high stereoselectivity and high yield of aliphatic chain alkyl substituted imine substrates, there are still two problems in this method at present, 1) it uses the NHC The carbene copper complex of tert-butoxide copper is used as a catalyst, which can only be prepared and stored in a specific place (such as a glove box), which limits its industrial application prospects; 2) Ellman's method is limited in substrate type There are limitations, usually the yield of alkylaminoboronic acid is good (yield: 74-88%), and the test found that the yield of arylaminoboronic acid is not good (yield: 52-61%), even had to to the target product;

Central to Ellman's approach is the stereochemical induction of Cu(I)-azcarbene-catalyzed boroester addition using a tert-butylsulfinamide substrate containing a chiral sulfoxide prosthetic group. Since Wanzlick and Ofele first reported azacarbene (NHC) and metal complexes in 1968, many stable and separable compounds of this type have been reported, and these compounds are often obtained when they catalyze organometallic reactions. Very good results, see literature 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) Report by Scott, N.M.; Nolan, S.P.Eur.J.Inorg.Chem.2005,1815-1828;

From the point of view of electron-donating strength, azacarbene is similar to electro-rich phosphine compounds, and is a kind of neutral 2-electron donor. It can form complexes with a variety of transition metals, and its coordination properties are similar to electron-rich organic phosphine ligands, but the stereochemical properties of the two are significantly different, see literature: 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. 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, 40, 4787-4790. Report;

The interaction with metals is dominated by σ-bonds, and the π feedback of metal d orbitals to carbene is relatively weak, which is a typical type of neutral σ-ligands, see literature: a) Bielawski, C.W.; Grubbs, R.H.Angew .Chem.Int.Ed.2000,39,2903-2906.b) Reported by Bielawski,C.W.;Benitez,D.;Grubbs,R.H.Science,2002,297,2041-2044.;

Reactions catalyzed by azacarbene (NHC) metal complexes have been successfully applied to Heck, Suzuki-Miyaura, Kumada, Sonogashira, Still, Negishi, Buchwald-Harting reactions, see literature:

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. 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

In 1993, the first case of Cu(I)-azacarbene (NHC) complex {[(NHC) ₂ Cu][O ₃ SCF ₃ ]} was reported, see literature: Arduengo, AJIII., Dias, HVR, Calabrese , reported by JC, Davidson, F., Organometallics, 1993, 12, 3405-3409.;

Literature: Jurkauskas, V., Sadighi, J.P., Buchwald, S.L., Org.Lett., 2003, 5, 2417-2420. report, Buchwald group prepared single NHC supported copper ( I) complexes prove that Cu(I)-azacarbene (NHC) complexes are typical two synergistic bodies, and its synergistic force also increases obviously along with the increase of the substituent on the nitrogen and the coordination ability of the metal. And apply it to the reduction of carbon-carbon double bonds of unsaturated carbonyl compounds, literature: Kang-SangLee, Adil, R.ZhugralinandAmirH.Hoveyda, J.Am.Chem.Soc., 2009, 131, 7253-7255. report , the Hoveyda group used azacarbene to catalyze the reaction of unsaturated carbonyl compounds and diboronic esters in the absence of metal salts to construct borate carbonyl compounds.

Looking at the construction method of aminoboronic acid, the use of azacarbene itself and its copper complex in catalyzing the addition of diborane reagents to carbon-heterodouble bonds, other research groups so far, from the mechanism of the reaction to the methodology There are certain vacancies and places that have not been explored clearly, especially the research on the reaction mechanism of azacarbene as a small molecule catalysis and the development of chiral azacarbene catalyst stereoselectivity in the construction of chiral aminoboronic acid research, and this field The research will directly promote the construction of such compound libraries and the development of the diversity of synthetic methods, which will play an extremely important role in the development of new drugs.

Contents of the invention

The purpose of this invention is to continue to disclose a variety of chiral aminoboronic acid derivatives and their preparation methods and applications on the basis of the previous patent application (application number: 201210194758.4), so as to overcome the above-mentioned defects in the prior art. Meet the needs of development in related fields.

The diverse chiral aminoboronic acid derivatives described in the present invention are compounds with the structure shown in formula (I):

in:

R and R combined are catechol esters, pinacol esters, dimethylamino esters, or (1S,2S,3R,5S) _- ( ₊ )-2,3-pinanediol esters; preferably For catechol esters.

R is selected from tert _- butylsulfinyl, benzyl, alkanoyloxy, aroyloxy, p-tolylsulfonyl, p-methoxyphenyl or p-nitrophenylsulfonyl; preferably tert-butyl Sulfinyl.

_R3 is selected from straight-chain alkane groups with 1-12 carbons, or cycloalkane groups with 3-12 carbons, branched alkane groups with 3-12 carbons, alkene groups with 2-6 carbons, and 2-6 carbons -Alkynes with 6 carbons, aromatic ring groups, aromatic heterocyclic groups, substituted linear alkane groups containing 1-12 carbons, or substituted cycloalkane groups with 3-12 carbons, substituted 1-12 carbons 2-6 carbon branched alkane groups, substituted alkenyl groups containing 2-6 carbons, substituted alkyne groups containing 2-6 carbons, substituted aromatic ring groups or substituted aromatic heterocyclic groups;

Preferably, _R3 is a straight-chain or branched alkane group containing 1-6 carbons, a cycloalkyl group containing 3-12 carbons, or a halogen-substituted, carbonyl-substituted, mercapto-substituted, hydroxyl-substituted, amino-substituted, ether group , carbonyl, aromatic ring group, amido group, guanidino group, nitro, cyano substituted or aromatic heterocyclic group substituted straight or branched chain alkane containing 1-6 carbons or cycloalkane containing 3-12 carbons Base, ring group or aromatic heterocyclic group, or halogen, carbonyl, mercapto, hydroxyl, amino, ether, carbonyl, amido, guanidino, nitro, cyano substituted aromatic ring or aromatic heterocyclic group; preferred , the aromatic ring group is phenyl, naphthyl or anthracenyl;

Preferably, the aromatic heterocyclic group is pyridyl, thienyl, pyrimidyl, pyrazinyl, pyrrolyl, tetrahydropyrrolyl, imidazolyl, naphthyl, anthracenyl, purinyl or indolyl.

R is selected from hydrogen, saturated or unsaturated cycloalkane groups with 1-8 carbons, nitrogen- or oxygen _- containing cyclic hydrocarbon groups, straight-chain or branched-chain alkane groups with 1-12 carbons, and 2-6 carbons Alkenyl group, alkyne group containing 2-6 carbons, aromatic ring group, aromatic heterocyclic group or halogen; said halogen is chlorine, bromine, iodine or fluorine; preferably chlorine;

Preferably, R is hydrogen or a branched or linear alkane group containing 1-6 carbons _;

The aromatic ring group is a substituted or unsubstituted phenyl, naphthyl or anthracenyl group, and the substituent is a 1-4 carbon saturated or unsaturated hydrocarbon group, hydroxyl group, methoxy group, trifluoromethyl group, amino group or halogen. The halogen is fluorine, chlorine or bromine, etc.;

The aromatic heterocyclic group is a substituted or unsubstituted pyridyl, pyrimidyl, pyrazinyl, pyrrolyl, purinyl, indolyl, and the substituent is a saturated or unsaturated hydrocarbon group with 1-4 carbons, hydroxyl, methoxy group, trifluoromethyl, amino or halogen, such as fluorine, chlorine or bromine, etc.;

Preferably, R is hydrogen or a branched or linear alkane group containing 1-6 carbons _;

Alternatively, R ₃ and R ₅ are jointly substituted or unsubstituted cyclic saturated or unsaturated aliphatic hydrocarbons with 3-10 carbons.

More preferably, R is hydrogen, methyl, ethyl, propyl or isopropyl _{; R} is hydrogen, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, isobutyl Base, tert-butyl, 3-chloropropyl, phenyl, benzyl, methoxybenzyl, fluorobenzyl, chlorobenzyl, methylphenyl, chlorophenyl, fluorophenyl, methyl Oxyphenyl, formyl, acetyl, p-phenol, benzyl, benzyl, p-benzyloxybenzyl, adamantyl, cyclopentyl, cyclohexyl, 3-p-methoxybenzyloxypropyl 4-phthalamidobutyl, methylamino, ethylamino, propylamino, butylamino, acetamido, formamido, hydroxymethyl, hydroxyethyl, hydroxypropyl, mercaptomethyl mercaptoethyl, mercaptopropyl, mercaptobutyl, thienyl, pyridyl, pyrimidinyl, imidazolyl, imidazolylmethyl, imidazolone, imidazolonemethyl, imidazoloneethyl, imidazolone Propyl, imidazolonylbutyl, pyrrolyl, tetrahydropyrrolyl, Boc (tert-butoxycarbonyl) or Ts (p-toluenesulfonyl) protected tetrahydropyrrolyl, furyl, indolyl, indole Methyl, guanidino, guanidinomethyl, guanidinoethyl, guanidinopropyl, purinyl, anthracenyl or naphthyl;

Or _R and R are jointly cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, p _- methylisopropylcyclohexyl, phenylcyclopropyl or cycloheptyl.

Preferably, the chiral aminoboronic acid of the diversity is:

The preparation method of the compound of formula (I) of the present invention comprises the following steps:

Under the catalysis of the azacarbene precursor and base, the imine compound shown by the general formula (I') and the diborane reagent are reacted in a protic solvent, and then the formula (I) is collected from the reaction product compound, the reaction temperature is 15-30°C, and the reaction time is 1-48 hours, preferably 24-48 hours.

Add ethyl acetate to the reacted mixture to dilute, and wash the organic layer; then extract the aqueous layer with ethyl acetate, combine the organic layers, dry and filter, and concentrate under reduced pressure; the product is purified by chromatography on silica gel or water-inactivated silica gel . The yield is 78-93.5%, and the optical purity is 98%.

The general reaction formula is as formula (V):

R, R ₁ , R ₂ , R ₄ and R ₅ are as defined above;

The base is selected from sodium tert-butoxide, sodium carbonate, potassium carbonate, triethylamine, 1,5-diazabicyclo[5,4,0]undecene-5, cesium fluoride, cesium carbonate or sodium hydride ;

Described protic solvent is selected from methanol, ethanol, isopropanol, pentapentyl alcohol, difluoroethanol, trifluoroethanol, difluoromethanol, trifluoromethanol, methyl mercaptan, ethanethiol, isopropyl mercaptan, water and Mixed solvents, etc.;

The azacarbene precursor is a compound with the following chemical structure:

Among them: R ₆ represents unsubstituted and substituted 1-6 carbon alkyl, substituted 1-6 carbon alkoxy, halogen, nitro, amino, substituted or acyclic benzene, aromatic ring or aromatic hetero ring, etc.; preferably hydrogen, 3-fluoro, 3-nitro, 3-methyl, ₃ -methoxy or benzo; M, Q are nitrogen or carbon; R represents 1-8 carbon alkyl, 1-8 carbon alkenyl groups, 1-8 carbon alkyne groups or aryl groups; X-represents fluorine, chlorine, bromine or iodide ion;

Ar ₁ represents phenyl, substituted phenyl or aromatic heterocyclic group, the substituent of substituted phenyl is methyl, fluorine, methoxy, cyano or nitro; aromatic heterocyclic group is pyridyl, 6-picoline Base, naphthyl, pyrazinyl, pyrrolyl, thienyl or pyrimidinyl;

Wherein, preferred azacarbene precursor is:

The preparation method of the azacarbene precursor can refer to the following patent (patent name: Diversified aryl imidazole quaternary ammonium salts and its preparation method and application, application number: 201210195065.7).

The preparation of the imine compound I' can be synthesized by referring to the general method of the literature (MaryAnnT.Robak, MelissaA.Herbage, and JonathanA.Ellman; Chemical Reviews, 2010, 110(6), 3609.), that is, various commercial aldehydes Or ketone compound and (R) - tert-butyl sulfinamide reaction. Its general reaction formula is:

Wherein R3 and R5 have the same definition as above, which are various commercial aldehydes or ketones. (R)-tert-butylsulfinamide and titanium tetraethoxide are commercial products.

Wherein, the chemical structure of representative imine compound I' is:

The diborane reagent (boronate) is a compound having a structure as shown in formula B:

Wherein: the definitions of R ₁ and R ₂ are the same as above.

The diborane reagent can be purchased commercially.

Preferably, the diborane reagent is selected from catechol esters, pinacol esters, dimethylamino esters, (1S,2S,3R,5S)-(+)-2,3-pinanediol (Pinanediol ) ester; the specific structure is as follows:

Pinacol Ester Diborane Catechol Ester Diborane Pinanediol Ester Diborane Dimethylamino Ester Diborane

The mol ratio of each component is as follows:

Compound I': diborane reagent: azacarbene ligand: base=1: 1～3: 0.05～0.2: 0.05～0.2;

The diverse chiral aminoboronic acid of the present invention can be used to prepare drugs for treating tumors or diabetes, and can also be used as intermediates for various drugs with important therapeutic effects (tumors, type 2 diabetes, hepatitis C, viruses, etc.), specifically related to As compound 4 prepared by the present invention can be used to prepare the myeloma inhibitor Bortezomib, the preparation method is as follows, see the literature MelissaA.Beenen, ChihuiAn, and JonathanA.Ellman; J.Am.Chem.Soc.2008,130,6910-6911 Report; As with the compound C-3 prepared by the present invention, by using a conventional deprotection method (reaction in 4N hydrogen chloride in methanol solution), the tert-butylsulfinyl group is removed to form the hydrochloride of proline boronic acid ester, It can be used to prepare the PT-100 of the American Phenomix company introduced in the preface. It is a very effective DPP-4 inhibitor and can be used as a promising drug for the treatment of type II diabetes. It has completed the Phase III clinical trial of the FDA. The preparation method References a) Snow, 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) George R. Lankas, et.al., Diabetes, 2005, 54, 2988-2994. Reported.

The beneficial effects of the present invention are: the diversity of chiral aminoboronic acids, many of the compounds involved in the preparation of the present invention cannot be prepared by other synthetic methods at present, and provide a rich library of this type of compounds for new drug research; according to the present invention The compound 4 prepared by the method can improve the yield and stereoselectivity, reduce the preparation cost of this type of drug and simplify the synthetic route. Has good economic benefits.

Detailed ways

The representative synthetic method of the addition of borate ester to tert-butylsulfinimide (general method 1):

Add 0.2mmol azacarbene precursor, ligand L-08' (0.1eq.), 0.2mmol cesium carbonate (0.1eq.), 2mmol tert-butylsulfinimide (1eq.), 2mmol borate ( 1eq.) and solvent methanol (20ml), added to the reaction flask (i.e. ligand, cesium carbonate, tert-butylsulfinimide and borate molar ratio is 1:1:1:1, ligand and solvent methanol The amount ratio is 1mmol: 200ml) The reaction solution is light yellow and stirred at room temperature for 24hr; the reaction progress is monitored by TLC. After the reaction was completed, ethyl acetate EA (30ml) was added for dilution, and the organic layer was washed with K ₂ CO ₃ . The aqueous layer was then extracted with EA (2 x 30ml). The combined organic layers _were dried over _Na2SO4 , filtered and concentrated under reduced pressure. The product is separated by column chromatography with deactivated silica gel (deactivated with water), and the developing solvent is chloroform/methanol system.

Example 1

Preparation and Characterization of Aminoboronate:

Take 294 mg (2 mmol) of tert-butylsulfinimide Compound 1', and use General Method 1 to react for 24 hours. The reaction mixture was purified by column chromatography on silica gel deactivated with water, and the developing solvent was chloroform/methanol system. The obtained product is a light yellow oily substance at room temperature, 468 mg (yield85%); ¹ HNMR (400MHz, DMSO-d ₆ , δ): 4.75 (d, J=5.6Hz, 1H), 2.86 (m, 1H) ,1.19(m,12H),1.16(d,J=7.2Hz,3H),1.09(s,9H); ¹³ CNMR(100MHz,DMSO-d ₆ ,δ):83.7,55.5,37.4,25.1,24.8, 23.1, 18.7; MS (ESI-TOF) m/z: 276.2 [M+H] ⁺ .

Example 2

Take 350mg (2mmol) of tert-butylsulfinimide Compound2', and use General Method 1 to react. React for 24 hours. The reaction mixture was purified by column chromatography on silica gel deactivated with water, and the developing solvent was chloroform/methanol system. The resulting product is a light yellow oily substance 551 mg (yield91%) at room temperature; ¹ HNMR (400MHz, D ₃ OD, δ): 2.97 (t, J=7.2Hz, 1H), 1.66 (m, 2H), 1.45(m,2H),1.29(d,J=3.2Hz,12H),1.23(s,9H),0.96(t,J=7.2Hz,3H); ¹³ CNMR(100MHz,CD ₃ OD,δ): 83.9, 55.9, 43.4, 35.3, 23.9, 23.6, 21.6, 19.6, 13.1; MS (ESI-TOF) m/z: 304.2 [M+H] ⁺ .

Example 3

Take 378mg (2mmol) of imine Compound 3', and use general method 1 to react.

React for 24 hours. The reaction mixture was purified by column chromatography on silica gel deactivated with water, and the developing solvent was chloroform/methanol system. The resulting product is a light yellow oil 558mg (yield88%) at room temperature; ¹ HNMR (400MHz, DMSO-d ₆ , δ): 4.31(d, J=8.0Hz, 1H), 2.54(d, J= 8.0Hz,1H),1.22(d,J=2.4Hz,12H),1.10(s,9H),0.93(s,9H); ¹³ CNMR(100MHz,DMSO-d ₆ ,δ):83.9,56.2,54.1 , 34.2, 28.1, 25.2, 24.9, 22.9; MS (ESI-TOF) m/z: 318.2 [M+H] ⁺ .

Example 4

Take 378mg (2mmol) of the imine Compound 4', and use the general method 1 to react. React for 24 hours. The reaction mixture was purified by column chromatography on silica gel deactivated with water, and the developing solvent was chloroform/methanol system. The obtained product is a colorless oily substance 545 mg (yield86%) at room temperature; ¹ HNMR (400MHz, DMSO-d ₆ , δ): 4.67 (d, J=6.0Hz, 1H), 2.80 (dd, J ₁ =8.0Hz,J ₂ =14.4Hz,1H),1.67(m,1H),1.41(m,2H),1.19(d,J=5.2Hz,12H),1.09(s,9H),0.86(dd, J ₁ =6.8Hz, J ₂ =2.4Hz,6H); ¹³ CNMR(100MHz,DMSO-d ₆ ,δ):83.7,55.6,42.2,25.4,25.1,24.8,23.1,23.1,23.0; MS(ESI- TOF) m/z: 318.2 [M+H] ⁺ .

Example 5

Add 402 mg (2 mmol) of imine Compound 5', and use General Method 1 to react for 24 hours. The reaction mixture was purified by column chromatography on silica gel deactivated with water, and the developing solvent was chloroform/methanol system. The obtained product is a light yellow oily substance 592 mg (yield90%) at room temperature; ¹ HNMR (400MHz, DMSO-d ₆ , δ): 4.58 (d, J=6.4Hz, 1H), 2.64 (dd, J ₁ =6.4Hz,J ₂ =8.4Hz,1H),2.03(m,1H),1.75(m,1H),1.64(m,1H),1.58(m,2H),1.49(m,2H),1.18( d,J=5.2Hz,12H),1.08(s,9H); ¹³ CNMR(100MHz,DMSO-d ₆ ,δ):83.7,55.8,47.0,42.7,30.9,29.6,25.5,25.4,25.2,25.1, 24.9, 24.8, 23.1; MS (ESI-TOF) m/z: 330.2 [M+H] ⁺ .

Example 6

Take 622mg (2mmol) of imine Compound8', and use general method 1 to react for 24 hours. The reaction mixture was purified by column chromatography on silica gel deactivated with water, and the developing solvent was chloroform/methanol system. The resulting product is a light yellow oil 729mg (yield83%) at room temperature; ¹ HNMR (400MHz, DMSO-d ₆ , δ): 7.24 (d, J=8.4Hz, 2H), 6.90 (d, J= 8.4Hz, 2H), 4.77(d, J=6.4Hz, 1H), 4.36(s, 2H), 3.74(s, 3H), 3.36(m, 2H), 2.76(d, J=6.4Hz, 1H) ,1.57(m,4H),1.19(d,J=2.8Hz,12H),1.08(s,9H); ¹³ CNMR(100MHz,DMSO-d ₆ ,δ):159.1,131.1,129.5,114.1,83.8, 71.9, 69.7, 55.4, 55.5, 42.4, 29.8, 27.1, 25.1, 24.8, 23.1; MS (ESI-TOF) m/z: 440.2 [M+H] ⁺ .

Example 7

Take 668mg (2mmol) of imine Compound9', and use General Method 1 to react for 24 hours. The reaction mixture was purified by column chromatography on silica gel deactivated with water, and the developing solvent was chloroform/methanol system. The obtained product is 785 mg (yield85%) of light yellow oil at room temperature; ¹ HNMR (400MHz, DMSO-d ₆ , δ): 7.85 (m, 4H), 4.70 (d, J=6.0Hz, 1H) ,3.57(t,J=6.8Hz,2H),1.56(m,4H),1.27(m,2H),1.10(d,J=5.2Hz,12H),1.08(s,9H); ¹³ CNMR(100MHz , DMSO-d ₆ , δ): 168.4, 134.8, 132.1, 123.4, 83.7, 55.6, 42.2, 37.8, 32.6, 28.4, 25.0, 24.7, 24.0, 23.0; MS (ESI-TOF) m/z: 463.2 [M +H] ⁺ .

Example 8

Take 446mg (2mmol) of imine Compound11', and use General Method 1 to react for 24 hours. The reaction mixture was purified by column chromatography on silica gel deactivated with water, and the developing solvent was chloroform/methanol system. The obtained product is a light yellow oily substance 604 mg (yield86%) at room temperature; ¹ HNMR (400MHz, DMSO-d ₆ , δ): 7.24 (m, 5H), 4.83 (d, J=5.2Hz, 1H) ,3.07(m,1H),2.95(m,1H),2.79(m,1H),1.10(s,15H),1.04(s,6H); ¹³ CNMR(100MHz,DMSO-d ₆ ,δ):139.2 , 129.6, 128.6, 126.7, 83.8, 55.7, 55.4, 43.6, 25.1, 24.7, 23.0; MS (ESI-TOF) m/z: 352.2 [M+H] ⁺ .

Example 9

Take 482mg (2mmol) of imine Compound12', and use general method 1 to react for 24 hours. The reaction mixture was purified by column chromatography on silica gel deactivated with water, and the developing solvent was chloroform/methanol system. The product obtained is a light yellow oil at room temperature, 649 mg (yield88%); ¹ HNMR (400MHz, DMSO-d ₆ , δ): 7.25 (dd, J ₁ =8.4Hz, J ₂ =6.0Hz, 2H) ,7.10(dd,J ₁ =9.2Hz,J ₂ =2.4Hz,2H),4.90(d,J=5.6Hz,1H),3.05(m,1H),2.92(m,1H),2.78(m, 1H),1.11(s,6H),1.08(s,9H),1.04(s,6H); ¹³ CNMR(100MHz,DMSO-d ₆ ,δ):161.3,135.4,131.4,115.2,83.8,55.7,43.8 , 38.2, 25.1, 24.7, 23.0; MS (ESI-TOF) m/z: 370.2 [M+H] ⁺ .

Example 10

The reaction was performed using General Method 1.

Add 446 mg (2 mmol) of imine Compound13' and react for 24 hours. The reaction mixture was purified by column chromatography on silica gel deactivated with water, and the developing solvent was chloroform/methanol system. The resulting product is a light yellow oil 597mg (yield85%) at room temperature; ¹ HNMR (400MHz, DMSO-d ₆ , δ): 7.20 (d, J=8.0Hz, 2H), 7.10 (d, J= 8.0Hz, 2H), 5.33(d, J=4.2Hz, 1H), 4.01(d, J=4.2Hz, 1H), 2.27(s, 3H), 1.13(s, 15H), 1.10(s, 6H) ; ¹³ CNMR(100MHz,DMSO-d ₆ ,δ):138.2,135.7,129.2,127.6,84.0,56.1,46.8,24.9,24.5,23.2,21.1; MS(ESI-TOF)m/z:352.2[M+ H] ⁺ .

Example 11

Take 486mg (2mmol) of imine Compound15', and use general method 1 to react for 24 hours. The reaction mixture was purified by column chromatography on silica gel deactivated with water, and the developing solvent was chloroform/methanol system. The obtained product is a light yellow oily substance at room temperature, 616 mg (yield83%); ¹ HNMR (400MHz, DMSO-d ₆ , δ): 7.36 (m, 4H), 5.57 (d, J=5.6Hz, 1H) ,4.08(d,J=5.6Hz,1H),1.14(s,15H),1.12(s,6H); ¹³ CNMR(100MHz,DMSO-d ₆ ,δ):104.7,131.3,129.4,128.5,84.3, 56.2, 46.8, 24.9, 24.5, 23.1; MS (ESI-TOF) m/z: 372.2 [M+H] ⁺ .

Example 12

Take 478mg (2mmol) of imine Compound18', and use General Method 1 to react for 24 hours. The reaction mixture was purified by column chromatography on silica gel deactivated with water, and the developing solvent was chloroform/methanol system. The resulting product is a light yellow oil 602mg (yield82%) at room temperature; ¹ HNMR (400MHz, DMSO-d ₆ , δ): 7.23 (d, J=8.8Hz, 2H), 6.87 (d, J= 8.8Hz, 2H), 5.27(d, J=5.2Hz, 1H), 3.99(d, J=5.2Hz, 1H), 3.72(s, 3H), 1.13(s, 15H), 1.11(s, 6H) ; ¹³ CNMR(100MHz,DMSO-d ₆ ,δ):158.4,133.1,128.9,114.1,84.0,56.1,55.5,46.8,24.9,24.5,23.1; MS(ESI-TOF)m/z:368.2[M+ H] ⁺ .

Example 13

Take 518mg (2mmol) of imine Compound18', and use General Method 1 to react for 24 hours. The reaction mixture was purified by column chromatography on silica gel deactivated with water, and the developing solvent was chloroform/methanol system. The resulting product is a light yellow oil 635 mg (yield82%) at room temperature; ¹ HNMR (400 MHz, DMSO-d ₆ , δ): 8.08 (m, 1H), 7.92 (m, 1H), 7.80 (m, 1H),7.66(m,1H),7.53(m,4H),5.55(d,J=5.6Hz,1H),4.76(d,J=5.6Hz,1H),1.18(s,9H),1.08( d,J=9.6Hz,12H); ¹³ CNMR(100MHz,DMSO-d ₆ ,δ):137.6,133.7,130.8,129.0,127.2,126.2,126.0,125.3,123.9,84.3,56.3,43.8,24.9,24.5 , 23.2; MS (ESI-TOF) m/z: 388.2 [M+H] ⁺ .

Example 14

Take 446mg (2mmol) of imine Compound25', and use General Method 1 to react for 24 hours. The reaction mixture was purified by column chromatography on silica gel deactivated with water, and the developing solvent was chloroform/methanol system. The resulting product is a light yellow oily substance 477mg (yield68%) at room temperature; ¹ HNMR (400MHz, DMSO-d ₆ , δ): 7.40 (m, 2H), 7.31 (m, 2H), 7.18 (m, 1H),5.18(s,0.34H),5.15(s,0.51H),1.64(s,1.22H),1.58(s,1.78H),1.20(s,9H),1.16(s,12H),1.13 (s,6H); ¹³ CNMR(100MHz,DMSO-d ₆ ,δ):146.2,146.1,128.3,128.2,127.2,126.3,126.2,84.4,84.2,56.7,55.8,25.0,24.9,24.9,24.6,24.4 , 23.4, 23.2; MS (ESI-TOF) m/z: 352.2 [M+H] ⁺ .

Example 15

Take 350mg (2mmol) of imine Compound26', and use General Method 1 to react for 24 hours. The reaction mixture was purified by column chromatography on silica gel deactivated with water, and the developing solvent was chloroform/methanol system. The resulting product is a light yellow oil 479mg (yield79%) at room temperature; ¹ HNMR (400MHz, DMSO-d ₆ , δ): 4.34(s, 0.65H), 1.63(m, 1H), 1.51(m ,1H),1.21(d,J=3.2Hz,12H),1.13(m,12H),0.84(t,J=7.2Hz,3H); ¹³ CNMR(100MHz,DMSO-d ₆ ,δ):84.1, 55.4, 32.7, 25.1, 24.9, 24.0, 23.0, 22.2; MS (ESI-TOF) m/z: 304.2 [M+H] ⁺ .

Example 16

(1) The compounds of Examples 1-15 were used for DPIV inhibition detection. The detection method was as follows: the samples were dissolved in 0.01M hydrochloric acid solution (pH=2), and a solution with a concentration of 1 mg/10 μl was prepared. Then mix the sample with 990 μl pH=8 buffer solution (containing 0.1mol/L hydroxyethylpiperazine ethanesulfonic acid HEPES and 0.14mol/L NaCl), and place the mixture at room temperature overnight. 20 μl of 2.5 μmol/L dipeptidyl peptidase IV (DPIV) solution was diluted with 40 ml of pH=8 buffer (same as above). The substrate is L-alanyl-L-proline-p-nitroaniline at a concentration of 0.1 mg/ml. Substrates and enzymes were placed in a 96-well plate, and the samples were added and incubated in a shaker at room temperature for 5 minutes, and then allowed to stand for 5 minutes, detected by 410nm light, and compared with the blank group.

(2) The compounds of Examples 1-15 were used to detect FAP inhibition by the 96-well plate method.

The results are shown in Table 1.

Table 1

Example compound IC ₅₀ (μM) DPIV (pH=8.0) FAP _IC50 (μM) 1 35 0.23 2 41 0.54 3 62 0.21 4 25 0.23 5 59 0.37 6 71 0.64 7 57 0.53 8 >100 8.1 9 43 0.48 10 59 0.72 11 40 0.15 12 39 0.66 13 89 0.87 14 96 0.30 15 35 0.22

Claims (2)

1. the application of chiral aminoboronic acid derivative in the medicine preparing treatment diabetes or tumour, it is characterized in that, the structural formula of described chiral aminoboronic acid derivative is such as formula shown in (I):

Wherein, R ₁and R ₂combine for pinacol ester; R ₄for terf-butylsulfinyl;

Described R ₅for hydrogen, methyl, ethyl, propyl group or sec.-propyl;

Described R ₃for methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, phenmethyl, mehtoxybenzyl, benzyl, chlorophenylmethyl, aminomethyl phenyl, chloro-phenyl-, fluorophenyl, p-methoxy-phenyl, cyclopentyl, 3-are to methoxyl group benzyloxy propyl group, 4-phthalyl amido butyl or naphthyl.

2. the preparation method of chiral aminoboronic acid derivative, is characterized in that, the structural formula of described chiral aminoboronic acid derivative is such as formula shown in (I):

Wherein, R ₁and R ₂combine for tetramethyl-ethylidene; R ₄for terf-butylsulfinyl;

Described R ₅for hydrogen, methyl, ethyl, propyl group or sec.-propyl;

Described R ₃for methyl, ethyl, propyl group, sec.-propyl, normal-butyl, sec-butyl, isobutyl-, the tertiary butyl, phenmethyl, mehtoxybenzyl, benzyl, chlorophenylmethyl, aminomethyl phenyl, chloro-phenyl-, fluorophenyl, p-methoxy-phenyl, cyclopentyl, 3-are to methoxyl group benzyloxy propyl group, 4-phthalyl amido butyl or naphthyl;

Comprise the steps:

Under azepine carbene precursor and base catalysis, the imine compound as shown in general formula (I ') and diboron hexahydride reagent are reacted in protic solvent, then from reaction product, collects formula I compound; Reaction expression is as follows:

Temperature of reaction is 15 ~ 30 DEG C, and the reaction times is 1 ~ 48 hour;

The amount ratio of described imine compound, diboron hexahydride reagent, azepine carbene precursor and alkali is 1:1 ~ 3:0.05 ~ 0.2:0.05 ~ 0.2; Described azepine carbene precursor is selected from following compound:

Described alkali is cesium carbonate, salt of wormwood or sodium carbonate; Described protic solvent is methyl alcohol;

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.