CN106831474B - One kind-the α containing alpha-aromatic, β-diamino acid ester derivant and its synthetic method and application - Google Patents

One kind-the α containing alpha-aromatic, β-diamino acid ester derivant and its synthetic method and application Download PDF

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CN106831474B
CN106831474B CN201710004520.3A CN201710004520A CN106831474B CN 106831474 B CN106831474 B CN 106831474B CN 201710004520 A CN201710004520 A CN 201710004520A CN 106831474 B CN106831474 B CN 106831474B
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CN106831474A (en
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刘顺英
雷锐锐
贾凯莉
吴永
刘冬岚
董素珍
胡文浩
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East China Normal University
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/49—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a carbon atom of an acyclic unsaturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C231/00—Preparation of carboxylic acid amides
    • C07C231/08—Preparation of carboxylic acid amides from amides by reaction at nitrogen atoms of carboxamide groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D307/00—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom
    • C07D307/02—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings
    • C07D307/34—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D307/38—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D307/54—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D333/00—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom
    • C07D333/02—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings
    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
    • C07D333/24—Radicals substituted by carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals

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Abstract

The invention discloses one kind-α containing alpha-aromatic, β-diamino acid ester derivant and its synthetic method, using aryl diazo compound, amide, imines as raw material, under the catalysis of metallic catalyst, in organic solvent,-the α containing alpha-aromatic, β-diamino acid ester derivant are obtained by single step reaction.Synthetic method of the present invention has high atom economy, highly selective advantage, and reaction condition is mild, safety easy to operate.- the α containing alpha-aromatic that the present invention is prepared, β-diamino acid ester derivant can be used as important chemical industry and medicine intermediate, and have bioactivity, suitable for preparing inhibitor against colon carcinoma cells and medicines resistant to liver cancer.

Description

One kind-the α containing alpha-aromatic, β-diamino acid ester derivant and its synthetic method and application
Technical field
The present invention relates to synthesis field of medicine and chemical technology, relate generally to one kind-α containing alpha-aromatic, β-diamino acid ester derivant And its quick, highly selective chemical synthesis process and application.
Background technique
α-quaternary carbon chiral centre amino acid (Cα- Tetrasubstituted α-amino acids) it is building natural products Therefore center framework with some important drugs are synthesized, synthesizes it with the biological activities such as antibacterial, antitumor, anticancer The research of method is always the hot subject of day hot research field and field of medicinal chemistry.In recent years, Takeo Kawabata resets to obtain asymmetric alpha-aromatic amino acid derivativges using the enol of Clayden ester (J.Am.Chem.Soc.2013,135,13294-13297)；Boris J.Nachtsheim has found that alkynyl salt compounded of iodine mediates Azlactones occur alkynylation reaction can quickly obtain α-quaternary carbon chiral centre amino acid derivatives (Org.Lett.2014, 16,1326-1329).Later successively also it has been found that novel synthesis, but these novel synthesis and route have step It is long, at high cost, time-consuming, low yield, operation and post-processing it is loaded down with trivial details the disadvantages of, be difficult to apply on a large scale in terms of industrialization, Economic value is limited.Therefore, the above method is all unfavorable for the-α containing alpha-aromatic, and β-diamino acid ester derivant is in organic synthesis Using and its industry be combined to.
Summary of the invention
The present invention overcomes the drawbacks described above of the prior art, propose one kind-α containing alpha-aromatic, β-diamino acid ester derivant And its synthetic method, the method preparation route are short, easy to operate, high-efficient.Method of the invention with aryl diazo compound, Amide, imines are raw material, under the effect of the catalyst ,-the α containing alpha-aromatic, β-diamino acid ester derivant are prepared.Phase Than in reported synthetic method, the present invention is using compound cheap and easy to get as raw material, the mild, reaction route with reaction condition It is short, reaction it is fast, at low cost, waste is few, easy to operate, Atom economy is high the features such as, synthetic method of the invention drug close There is broad prospect of application at field.
- the α proposed by the present invention containing alpha-aromatic, β-diamino acid ester derivant, as shown in formula (I),
Wherein,
Ar is aryl, phenyl, the methoxy-substituted phenyl, three that phenyl, the nitro replaced selected from phenyl, halogen replaces Phenyl, the alkyl-substituted phenyl of C1-C10 of methyl fluoride substitution；
R1For hydrogen, C1-C10 alkyl, phenyl, the alkyl-substituted phenyl of C1-C10, benzyl；
R2For the alkyl-substituted alkynyl of C1-C10, the alkyl-substituted alkenyl of C1-C10, C1-C10 alkyl；
R3For with halogen, C1-C10 alkyl, nitro, methoxyl group, trifluoromethyl, ester group phenyl ring, furan nucleus, thiophene Ring, pyrrole ring, 2- methyl benzoate base.
Preferably,
Ar is aryl, is selected from phenyl, 4- chlorphenyl, 3- chlorphenyl, 2- chlorphenyl, 4- nitrobenzophenone, 3- fluorophenyl, 2- Methoxyphenyl；
R1For hydrogen, methyl, ethyl, toluene, benzyl；
R2For acetylene, ethylene, methyl, ethyl；
R3For 4- nitrobenzophenone, 4- fluorophenyl, 3- fluorophenyl, 2- fluorophenyl, 4- bromophenyl, 3- bromophenyl, 2- bromophenyl, The bromo- 4- fluorophenyl of 4- chlorphenyl, 3- chlorphenyl, 3-, 1,2- dichlorophenyl, trifluoromethyl, furan nucleus, 2- methyl benzoate Base.
It is further preferred that
Ar is aryl, is selected from phenyl, 4- chlorphenyl, 3- chlorphenyl；
R1For methyl；
R2For acetylene, ethylene, methyl, ethyl；
R3For 4- nitrobenzophenone, 4- fluorophenyl, 3- bromophenyl, 2- bromophenyl, bromo- 4 fluorophenyl of 3-, trifluoromethyl, Furan nucleus, 2- methyl benzoate base.
The present invention proposes one kind-α containing alpha-aromatic, β-diamino acid ester derivant synthetic method, with aryl shown in formula (1) Amide shown in diazonium compound, formula (2), imines shown in formula (3) they are raw material, in organic solvent,Molecular sieve (MS it) deposits Under lower and nitrogen protection, under the action of metallic catalyst ,-the α containing alpha-aromatic shown in formula (I) is prepared through single step reaction, β-diamino acid ester derivant.Wherein, the method need to carry out under water-less environment,The effect of molecular sieve is water removal, nitrogen Protection is lower to be taken a breath by oil pump, prevents air from entering reaction system.
Specifically, the method are as follows: by imines shown in formula (3), rhodium acetate,Molecular sieve is dissolved in organic solvent, is configured to Mixed solution A；Amide shown in aryl diazo compound shown in formula (1), formula (2) is dissolved in organic solvent and is configured to mixed solution B； Mixed solution B is slowly added in mixed solution A；Reacted, purifying obtains shown in the formula (I) of high cis-selectivity containing α-virtue Base-α, β-diamino acid ester derivant, shown in the synthetic reaction such as formula (II):
Wherein,
Ar is aryl, phenyl, the methoxy-substituted phenyl, three that phenyl, the nitro replaced selected from phenyl, halogen replaces Phenyl, the alkyl-substituted phenyl of C1-C10 of methyl fluoride substitution；
R1For hydrogen, C1-C10 alkyl, phenyl, the alkyl-substituted phenyl of C1-C10, benzyl；
R2For the alkyl-substituted alkynyl of C1-C10, the alkyl-substituted alkenyl of C1-C10, C1-C10 alkyl；
R3For with halogen, C1-C10 alkyl, nitro, methoxyl group, trifluoromethyl, ester group phenyl ring, furan nucleus, thiophene Ring, pyrrole ring, 2- methyl benzoate base；
Preferably,
Ar is aryl, is selected from phenyl, 4- chlorphenyl, 3- chlorphenyl, 2- chlorphenyl, 4- nitrobenzophenone, 3- fluorophenyl, 2- Methoxyphenyl；
R1For hydrogen, methyl, ethyl, toluene, benzyl；
R2For acetylene, ethylene, methyl, ethyl；
R3For 4- nitrobenzophenone, 4- fluorophenyl, 3- fluorophenyl, 2- fluorophenyl, 4- bromophenyl, 3- bromophenyl, 2- bromophenyl, The bromo- 4- fluorophenyl of 4- chlorphenyl, 3- chlorphenyl, 3-, 1,2- dichlorophenyl, trifluoromethyl, furan nucleus, 2- methyl benzoate Base.
It is further preferred that
Ar is aryl, is selected from phenyl, 4- chlorphenyl, 3- chlorphenyl；
R1For methyl；
R2For acetylene, ethylene, methyl, ethyl；
R3For 4- nitrobenzophenone, 4- fluorophenyl, 3- bromophenyl, 2- bromophenyl, bromo- 4 fluorophenyl of 3-, trifluoromethyl, Furan nucleus, 2- methyl benzoate base.
In the method for the present invention, the aryl diazo compound, amide, imines and rhodium acetate inventory molar ratio be aryl Diazonium compound: amide: imines: rhodium acetate=1.0:0.8~1.5:1.0~1.5:0.05~0.20, it is preferable that aryldiazonium Compound: amide: imines: the molar ratio of rhodium acetate is 1.0:1.0:1.2:0.1.
In the method for the present invention, the usage ratio of organic solvent and aryl diazo compound is 5mL~10mL:1mmol.It is preferred that The usage ratio of ground, organic solvent and aryl diazo compound is 10mL:1mmol.
In the method for the present invention, the reaction temperature is -20~120 DEG C.Preferably, the reaction temperature is 25 DEG C.
In the method for the present invention, the reaction time be 2~for 24 hours.Preferably, the reaction time is 3~12h.
In the method for the present invention, the aryl diazo compound is aryldiazonium ester compound.
In the method for the present invention, the organic solvent includes methylene chloride, chloroform, toluene, tetrahydrofuran, acetic acid second Ester, 1,2- dichloroethanes.Preferably, the organic solvent is anhydrous methylene chloride.
In the method for the present invention, shown catalyst is metallic catalyst, mixed selected from rhodium acetate or rhodium acetate and chiral phosphoric acid Close object；Preferably, the metallic catalyst is rhodium acetate or is urged altogether with the mixture of molar ratio 1:10 rhodium acetate and chiral phosphoric acid Change.
In a specific embodiment, the present invention-α containing alpha-aromatic, β-diamino acid ester derivant synthetic method, packet Include following steps: aryl diazo compound: amide: imines: rhodium acetate=1.0:1.0:1.2:0.1 molar ratio is (with aryldiazonium On the basis of compound amount), weigh raw material.By imines, rhodium acetate andMolecular sieve is dissolved in organic solvent (added with N before solvent2 Protect lower oil pump ventilation), it is configured to mixed solution A；Aryl diazo compound and amide are dissolved in organic solvent, are configured to mix Solution B；At room temperature, mixed solution A is added in mixed solution B syringe pump, be vigorously stirred simultaneously；Diazo solution drop After adding, continue stirring at room temperature 3~12 hours, until the consumption of diazoamines compound is complete；Crude product is subjected to column layer Analysis (using petroleum ether: ethyl acetate=10:1~5:1~3:1 is eluant, eluent) obtains net product formula (I)-α containing alpha-aromatic, β-diamino Base acid ester derivant.
The invention also provides the formula being prepared according to synthetic method of the present invention (I)-α containing alpha-aromatic, β-diamino acid esters Derivative.
The invention also provides formula (I)-α containing alpha-aromatic, β-diamino acid ester derivants in the preparation of antitumor drugs Using.
The invention also provides-the α containing alpha-aromatic shown in formula (I), β-diamino acid ester derivant is preparing inhibitor against colon carcinoma cells, is resisting Application in liver-cancer medicine.
The invention also provides-the α containing alpha-aromatic shown in formula (I), β-diamino acid ester derivant is preparing inhibitor against colon carcinoma cells HCT116 cell, anti-liver cancer and anti-BEL7402 cell, the application in anti-liver cancer and anti-SMMC7721 cell drug.
The present invention-α containing alpha-aromatic, β-diamino acid ester derivant are important chemical industry and medicine intermediate, in medicineization Work field is widely applied, and has very big application prospect.Synthetic method of the invention has using compound cheap and easy to get as raw material Reaction condition is mild, reaction step is few, reaction is fast, waste at low cost, generating is few, safety easy to operate, Atom economy are high, The high beneficial effect of selectivity.
Detailed description of the invention
Fig. 1 is 1 products therefrom of embodiment1H NMR schematic diagram.
Fig. 2 is 1 products therefrom of embodiment13C NMR schematic diagram.
Fig. 3 is that the HPLC of 1 products therefrom of embodiment schemes.
Fig. 4 is 2 products therefrom of embodiment1H NMR schematic diagram.
Fig. 5 is 2 products therefrom of embodiment13C NMR schematic diagram.
Fig. 6 is that the HPLC of 2 products therefrom of embodiment schemes.
Fig. 7 is 3 products therefrom of embodiment1H NMR schematic diagram.
Fig. 8 is 3 products therefrom of embodiment13C NMR schematic diagram.
Fig. 9 is 3 products therefrom HPLC of embodiment figure.
Figure 10 is 4 products therefrom of embodiment1H NMR schematic diagram.
Figure 11 is 4 products therefrom of embodiment13C NMR schematic diagram.
Figure 12 is 4 products therefrom of embodiment19F NMR schematic diagram.
Figure 13 is 4 products therefrom HPLC of embodiment figure.
Figure 14 is 5 products therefrom of embodiment1H NMR schematic diagram.
Figure 15 is 5 products therefrom of embodiment13C NMR schematic diagram.
Figure 16 is 5 products therefrom HPLC of embodiment figure.
Figure 17 is 6 products therefrom of embodiment1H NMR schematic diagram.
Figure 18 is 6 products therefrom of embodiment13C NMR schematic diagram.
Figure 19 is 6 products therefrom of embodiment19F NMR schematic diagram.
Figure 20 is that the HPLC of 6 products therefrom of embodiment schemes.
Figure 21 is 7 products therefrom of embodiment1H NMR schematic diagram.
Figure 22 is 7 products therefrom of embodiment13C NMR schematic diagram.
Figure 23 is 7 products therefrom of embodiment19F NMR schematic diagram.
Figure 24 is that the HPLC of 7 products therefrom of embodiment schemes.
Figure 25 is 8 products therefrom of embodiment1H NMR schematic diagram.
Figure 26 is 8 products therefrom of embodiment13C NMR schematic diagram.
Figure 27 is 8 products therefrom HPLC of embodiment figure.
Figure 28 is 9 products therefrom of embodiment1H NMR schematic diagram.
Figure 29 is 9 products therefrom of embodiment13C NMR schematic diagram.
Figure 30 is 9 products therefrom HPLC of embodiment figure.
Figure 31 is 10 products therefrom of embodiment1H NMR schematic diagram.
Figure 32 is 10 products therefrom of embodiment13C NMR schematic diagram.
Figure 33 is 10 products therefrom HPLC of embodiment figure.
Figure 34 is 11 products therefrom of embodiment1H NMR schematic diagram.
Figure 35 is 11 products therefrom of embodiment13C NMR schematic diagram.
Figure 36 is that the HPLC of 11 products therefrom of embodiment schemes.
Figure 37 is 12 products therefrom of embodiment1H NMR schematic diagram.
Figure 38 is 12 products therefrom of embodiment13C NMR schematic diagram.
Figure 39 is that the HPLC of 12 products therefrom of embodiment schemes.
Figure 40 is 13 products therefrom of embodiment1H NMR schematic diagram.
Figure 41 is 13 products therefrom of embodiment13C NMR schematic diagram.
Figure 42 is 13 products therefrom HPLC of embodiment figure.
Figure 43 is 14 products therefrom of embodiment1H NMR schematic diagram.
Figure 44 is 14 products therefrom of embodiment13C NMR schematic diagram.
Figure 45 is 14 products therefrom HPLC of embodiment figure.
Figure 46 is 15 products therefrom of embodiment1H NMR schematic diagram.
Figure 47 is 15 products therefrom of embodiment13C NMR schematic diagram.
Figure 48 is 15 products therefrom HPLC of embodiment figure.
Specific embodiment
In conjunction with following specific embodiments and attached drawing, the present invention is described in further detail, protection content of the invention It is not limited to following embodiment.Without departing from the spirit and scope of the invention, those skilled in the art it is conceivable that change Change and advantage is all included in the present invention, and using appended claims as protection scope.Implement process of the invention, Condition, reagent, experimental method etc. are among the general principles and common general knowledge in the art in addition to what is specifically mentioned below, There are no special restrictions to content by the present invention.
The present invention synthesizes the-α containing alpha-aromatic, β-diamino acid ester derivant preparation method, reaction process such as formula (II) institute Show:
Ar is aryl, phenyl, the methoxy-substituted phenyl, three that phenyl, the nitro replaced selected from phenyl, halogen replaces Phenyl, the alkyl-substituted phenyl of C1-C10 of methyl fluoride substitution；
R1For hydrogen, C1-C10 alkyl, phenyl, the alkyl-substituted phenyl of C1-C10, benzyl；
R2For the alkyl-substituted alkynyl of C1-C10, the alkyl-substituted alkenyl of C1-C10, C1-C10 alkyl；
R3For with halogen, C1-C10 alkyl, nitro, methoxyl group, trifluoromethyl, ester group phenyl ring, furan nucleus, thiophene Ring, pyrrole ring, 2- methyl benzoate base.
Embodiment 1
By imines (0.24mmol), rhodium acetate (0.0024mmol) andMolecular sieve (300mg) is mixed in 10mL single port bottle In, oil pump carries out nitrogen ventilation, and 1mL is added with 1mL syringe and steams CH again2Cl2Solution is configured to mixed solution A, at room temperature Stirring 10 minutes.Aryl diazo compound (0.2mmol) and amide compound (0.2mmol) are dissolved in 1mL and steam CH again again2Cl2It is molten Liquid is configured to solution B.By solution B at 25 DEG C, mixed solution A is added with syringe pump in 1 hour.Stirring 3~12 hours, Reaction mixture is purified by column chromatography, obtains net product, is methyl (2S, 3S) -3- (4- shown in structure such as formula (a) Nitrobenzophenone) -3- ((2- hydroxy phenyl) amino) -2- phenyl -2- propine amide methyl propionate, yield 87%, dr value is equal to 89:11, HPLC purity are 96%.Compound shown in formula (a)1H NMR schematic diagram as shown in Figure 1, its13C NMR schematic diagram is such as Shown in Fig. 2, HPLC schematic diagram is as shown in Figure 3.
1H NMR (400MHz, DMSO) δ 9.60 (s, 1H), 9.31 (s, 1H), 8.10 (d, J=8.2Hz, 2H), 7.51- 7.29 (m, 7H), 6.59 (d, J=7.3Hz, 1H), 6.45 (t, J=7.2Hz, 1H), 6.36 (t, J=7.3Hz, 1H), 6.25 (d, J=7.2Hz, 1H), 5.78 (d, J=7.7Hz, 1H), 5.60 (d, J=7.7Hz, 1H), 4.36 (s, 1H), 3.57 (s, 3H).13C NMR(100MHz,DMSO)δ169.40,151.84,147.12,146.85,144.28,136.25,135.00, 129.94,128.02,127.93,126.89,122.68,119.35,116.67,113.44,110.46,77.71,77.54, 69.09,61.17,52.74.HRMS(ESI):Calcd.for C25H21N3O6Na[M+Na]+:482.1328,Found: 482.1322.
Embodiment 2
By imines (0.24mmol), rhodium acetate (0.0024mmol) andMolecular sieve (300mg) is mixed in 10mL single port bottle In, oil pump carries out nitrogen ventilation, and 1mL is added with 1mL syringe and steams CH again2Cl2Solution is configured to mixed solution A, at room temperature Stirring 10 minutes.Aryl diazo compound (0.2mmol) and amide compound (0.2mmol) are dissolved in 1mL and steam CH again again2Cl2It is molten Liquid is configured to solution B.By solution B at 25 DEG C, mixed solution A is added with syringe pump in 1 hour.Stirring 3~12 hours, Reaction mixture is purified by column chromatography, obtains net product, is methyl (2S, 3S) -3- (2- shown in structure such as formula (b) Bromophenyl) -3- ((2- hydroxy phenyl) amino) -2- phenyl -2- propine amide methyl propionate, yield 54%, dr value is equal to 94: 6, HPLC purity are 95%.Compound shown in formula (b)1H NMR schematic diagram as shown in figure 4, its13C NMR schematic diagram such as Fig. 5 institute Show, HPLC schematic diagram is as shown in Figure 6.
1H NMR (400MHz, DMSO) δ 10.03 (s, 1H), 9.40 (s, 1H), 7.43-7.11 (m, 9H), 6.61 (d, J= 7.5Hz, 1H), 6.44 (t, J=7.4Hz, 1H), 6.34 (t, J=7.3Hz, 1H), 6.20 (dd, J=12.6,8.3Hz, 2H), 5.29 (d, J=8.5Hz, 1H), 4.40 (s, 1H), 3.67 (s, 3H)13C NMR(100MHz,DMSO)δ168.85,151.52, 144.25,136.93,136.09,135.02,131.86,129.76,129.29,128.12,127.61,127.40,127.13, 126.85,119.26,116.54,113.37,110.59,77.75,77.56,67.83,61.04,52.60.HRMS(ESI): Calcd.for C25H21BrN2O4Na[M+Na]+:515.0582,Found:515.0608.
Embodiment 3
By imines (0.24mmol), rhodium acetate (0.0024mmol) andMolecular sieve (300mg) is mixed in 10mL single port bottle In, oil pump carries out nitrogen ventilation, and 1mL is added with 1mL syringe and steams CH again2Cl2Solution is configured to mixed solution A, at room temperature Stirring 10 minutes.Aryl diazo compound (0.2mmol) and amide compound (0.2mmol) are dissolved in 1mL and steam CH again again2Cl2It is molten Liquid is configured to solution B.By solution B at 25 DEG C, mixed solution A is added with syringe pump in 1 hour.Stirring 3~12 hours, Reaction mixture is purified by column chromatography, obtains net product, is methyl (2S, 3S) -3- (3- shown in structure such as formula (c) Bromophenyl) -3- ((2- hydroxy phenyl) amino) -2- phenyl -2- propine amide methyl propionate, yield 70%, dr value is equal to 95: 5, HPLC purity are 97%.Compound shown in formula (c)1H NMR schematic diagram as shown in fig. 7, its13C NMR schematic diagram such as Fig. 8 institute Show, HPLC schematic diagram is as shown in Figure 9.
1H NMR (400MHz, DMSO) δ 9.43 (s, 1H), 9.28 (s, 1H), 7.45-7.11 (m, 9H), 6.59 (d, J= 6.9Hz, 1H), 6.46 (t, 1H), 6.37 (t, 1H), 6.27 (d, J=6.9Hz, 1H), 5.74 (d, J=6.5Hz, 1H), 5.39 (d, J=6.5Hz, 1H), 4.37 (s, 1H), 3.57 (s, 3H)13C NMR(100MHz,DMSO)δ169.54,151.82, 151.74,144.24,144.10,141.49,136.29,135.24,131.13,130.37,129.74,127.84,127.61, 127.03,121.14,119.40,116.51,113.41,110.49,77.58,69.25,61.25,52.67.HRMS(ESI): Calcd.for C25H21BrN2O4Na[M+Na]+:515.0582,Found:515.0582.
Embodiment 4
By imines (0.24mmol), rhodium acetate (0.0024mmol) andMolecular sieve (300mg) is mixed in 10mL single port bottle In, oil pump carries out nitrogen ventilation, and 1mL is added with 1mL syringe and steams CH again2Cl2Solution is configured to mixed solution A, at room temperature Stirring 10 minutes.Aryl diazo compound (0.2mmol) and amide compound (0.2mmol) are dissolved in 1mL and steam CH again again2Cl2It is molten Liquid is configured to solution B.By solution B at 25 DEG C, mixed solution A is added with syringe pump in 1 hour.Stirring 3~12 hours, Reaction mixture is purified by column chromatography, obtains net product, is methyl (2S, 3S) -3- (4- shown in structure such as formula (d) Fluorophenyl) -3- ((2- hydroxy phenyl) amino) -2- phenyl -2- propine amide methyl propionate, yield 93%, dr value is equal to 90: 10, HPLC purity are 99%.Compound shown in formula (d)1H NMR schematic diagram is as shown in Figure 10,13C NMR schematic diagram is as schemed Shown in 11,19F NMR schematic diagram is as shown in figure 12, and HPLC schematic diagram is as shown in figure 13.
1H NMR(400MHz,DMSO)δ9.32(s,1H),9.23(s,1H),7.40–7.25(m,5H),7.12(m,2H), 7.04 (m, 2H), 6.58 (dd, J=7.5,1.28Hz, 1H), 6.45 (t, J=7.1Hz, 1H), 6.38-6.30 (t, J=7.5, 1H), 6.23 (d, J=7.1Hz, 1H), 5.80 (d, J=8.0Hz, 1H), 5.36 (d, J=8.0Hz, 1H), 4.34 (s, 1H), 3.59(s,3H).13C NMR (100MHz, DMSO) δ 169.59,161.48 (d, J=243.6Hz), 151.74,144.26, (136.48,135.38,134.49,130.28 d, J=8.3Hz), 127.74 (d, J=7.5Hz), 127.14,119.33, (116.33,114.45 d, J=21.2Hz), 113.33,110.51,77.69,77.50,69.25,61.18,52.71.19F NMR (376MHz,DMSO)δ-115.08.HRMS(ESI):Calcd.for C25H22FN2O4Na[M+Na]+:455.1383,Found: 455.1369.
Embodiment 5
By imines (0.24mmol), rhodium acetate (0.0024mmol) andMolecular sieve (300mg) is mixed in 10mL single port bottle In, oil pump carries out nitrogen ventilation, and 1mL is added with 1mL syringe and steams CH again2Cl2Solution is configured to mixed solution A, at room temperature Stirring 10 minutes.Aryl diazo compound (0.2mmol) and amide compound (0.2mmol) are dissolved in 1mL and steam CH again again2Cl2It is molten Liquid is configured to solution B.By solution B at 25 DEG C, mixed solution A is added with syringe pump in 1 hour.Stirring 3~12 hours, Reaction mixture is purified by column chromatography, obtains net product, is methyl (2S, 3S) -3- (4- shown in structure such as formula (e) Aminomethyl phenyl) -3- ((2- hydroxy phenyl) amino) -2- phenyl -2- propine amide methyl propionate, yield 78%, dr value is equal to 89:11, HPLC purity are 99%.Compound shown in formula (e)1H NMR schematic diagram is as shown in figure 14,13C NMR schematic diagram is such as Shown in Figure 15, HPLC schematic diagram is as shown in figure 16.
1H NMR (400MHz, DMSO) δ 9.21 (s, 1H), 9.09 (s, 1H), 7.44-7.21 (m, 5H), 7.01 (d, J= 7.7Hz, 2H), 6.94 (d, J=7.7Hz, 2H), 6.58 (d, J=7.4Hz, 1H), 6.44 (t, J=7.6Hz, 1H), 6.33 (t, J=7.4Hz, 1H), 6.22 (d, J=7.6Hz, 1H), 5.90 (d, J=7.8Hz, 1H), 5.29 (d, J=7.8Hz, 1H), 4.34 (s,1H),3.61(s,3H),2.22(s,3H).13C NMR(100MHz,DMSO)δ169.71,151.70,144.23,136.64, 136.45,135.60,135.18,128.36,128.21,127.70,127.65,127.31,119.31,116.09,113.26, 110.41,77.73,77.49,69.36,61.60,52.79,20.61.HRMS(ESI):Calcd.for C26H24N2O4Na[M+ Na]+:451.1634,Found:451.1640.
Embodiment 6
By imines (0.24mmol), rhodium acetate (0.0024mmol) andMolecular sieve (300mg) is mixed in 10mL single port bottle In, oil pump carries out nitrogen ventilation, and 1mL is added with 1mL syringe and steams CH again2Cl2Solution is configured to mixed solution A, at room temperature Stirring 10 minutes.Aryl diazo compound (0.2mmol) and amide compound (0.2mmol) are dissolved in 1mL and steam CH again again2Cl2It is molten Liquid is configured to solution B.By solution B at 25 DEG C, mixed solution A is added with syringe pump in 1 hour.Stirring 3~12 hours, Reaction mixture is purified by column chromatography, obtains net product, is methyl (2S, 3S) -3- (4- shown in structure such as formula (f) Trifluoromethyl) -3- ((2- hydroxy phenyl) amino) -2- phenyl -2- propine amide methyl propionate, yield 70%, dr value Equal to 95:5, HPLC purity is 97%.Compound shown in formula (f)1H NMR schematic diagram is as shown in figure 17,13C NMR signal Figure as shown in figure 18 its19F NMR schematic diagram is as shown in figure 19, and HPLC schematic diagram is as shown in figure 20.
1H NMR (400MHz, DMSO) δ 9.46 (s, 1H), 9.27 (s, 1H), 7.60 (d, J=7.9Hz, 2H), 7.34 (m, 7H), 6.58 (d, J=7.6Hz, 1H), 6.44 (d, J=7.5Hz, 1H), 6.35 (t, J=7.5Hz, 1H), 6.23 (d, J= 7.7Hz, 1H), 5.83 (d, J=7.9Hz, 1H), 5.51 (d, J=7.9Hz, 1H), 4.36 (s, 1H), 3.59 (s, 3H)13C NMR(100MHz,DMSO)δ169.49,151.85,144.26,143.62,136.29,135.20,129.33,127.88(d,J =6.7Hz), 127.01,124.54,119.35,116.49,113.39,110.35,77.65,77.61,69 .19,61.26, 52.75.19F NMR(376MHz, DMSO)δ-60.81.HRMS(ESI):Calcd.for C26H21F3N2O4Na[M+Na]+: 505.1351,Found:505.1331.
Embodiment 7
By imines (0.24mmol), rhodium acetate (0.0024mmol) andMolecular sieve (300mg) is mixed in 10mL single port bottle In, oil pump carries out nitrogen ventilation, and 1mL is added with 1mL syringe and steams CH again2Cl2Solution is configured to mixed solution A, at room temperature Stirring 10 minutes.Aryl diazo compound (0.2mmol) and amide compound (0.2mmol) are dissolved in 1mL and steam CH again again2Cl2It is molten Liquid is configured to solution B.By solution B at 25 DEG C, mixed solution A is added with syringe pump in 1 hour.Stirring 3~12 hours, Reaction mixture is purified by column chromatography, obtains net product, is methyl (2S, 3S) -3- (3- shown in structure such as formula (g) Bromo- 4- fluoro-phenyl) -3- ((2- hydroxy phenyl) amino) -2- phenyl -2- propine amide methyl propionate, yield 77%, dr value Equal to > 95:5, HPLC purity is 99%.Compound shown in formula (g)1H NMR schematic diagram is as shown in figure 21,13C NMR signal Figure is as shown in figure 22,19Its HPLC schematic diagram is as shown in figure 24 as shown in figure 23 for F NMR schematic diagram.
1H NMR (400MHz, DMSO) δ 10.05 (s, 1H), 9.41 (s, 1H), 7.41-7.13 (m, 8H), 6.62 (d, J= 7.5Hz, 1H), 6.44 (t, J=7.3Hz, 1H), 6.37 (t, J=7.5Hz, 1H), 6.15 (dd, J=7.3,3.4Hz, 2H), 5.27 (d, J=8.2Hz, 1H), 4.40 (s, 1H), 3.67 (s, 3H)13C NMR(100MHz,DMSO)δ168.83,160.94 (d, J=249.3Hz), 151.59,144.30,136.07,134.89,133.44 (d, J=3.3Hz), 130.68 (d, J= 8.9Hz), 128.05,127.47,127.26,126.76 (d, J=9.6Hz), 119.28,118.69 (d, J=24.3Hz), (116.71,114.96 d, J=21.1Hz), 113.44,110.55,77.72,77.61,67.86,60.52,52.65.19F NMR (376MHz,DMSO)δ-112.05,-112.06.HRMS(ESI):Calcd.for C25H20FBrN2O4Na[M+Na]+: 533.0488,Found:533.0514.
Embodiment 8
By imines (0.24mmol), rhodium acetate (0.0024mmol) andMolecular sieve (300mg) mixing and 10mL single port bottle In, oil pump carries out nitrogen ventilation, and 1mL is added with 1mL syringe and steams CH again2Cl2Solution is configured to mixed solution A, at room temperature Stirring 10 minutes.Aryl diazo compound (0.2mmol) and amide compound (0.2mmol) are dissolved in 1mL and steam CH again again2Cl2It is molten Liquid is configured to solution B.By solution B at 25 DEG C, mixed solution A is added with syringe pump in 1 hour.Stirring 3~12 hours, Reaction mixture is purified by column chromatography, obtains net product, is methyl (2S, 3S) -3- shown in structure such as formula (h) ((2- hydroxy phenyl) amino) -2- phenyl -2- propine amide -3- (thiophene -2- base) methyl propionate, yield 58%, dr value etc. In > 95:5, HPLC purity is 98%.Compound shown in formula (h)1H NMR schematic diagram is as shown in figure 25,13C NMR schematic diagram As shown in figure 26, HPLC schematic diagram is as shown in figure 27.
1H NMR(400MHz,DMSO)δ9.23(s,1H),9.21(s,1H),7.33(m,6H),6.93–6.88(m,1H), 6.85 (d, J=2.8Hz, 1H), 6.60 (d, J=7.6Hz, 1H), 6.52 (t, J=7.2Hz, 1H), 6.39 (dd, J=11.8, 7.6Hz,2H),5.73(s,2H),4.36(s,1H),3.62(s,3H).13C NMR(100MHz,DMSO)δ169.70,151.84, 144.30,143.29,135.68,135.53,127.94,127.01,126.38,126.31,125.82,119.36,116.72, 113.39,110.43,77.74,77.58,69.76,58.08,52.94.HRMS(ESI):Calcd.for C23H20SN2O4Na[M +Na]+:433.1041,Found:433.1042.
Embodiment 9
By imines (0.24mmol), rhodium acetate (0.0024mmol) andMolecular sieve (300mg) is mixed in 10mL single port bottle In, oil pump carries out nitrogen ventilation, and 1mL is added with 1mL syringe and steams CH again2Cl2Solution is configured to mixed solution A, at room temperature Stirring 10 minutes.Aryl diazo compound (0.2mmol) and amide compound (0.2mmol) are dissolved in 1mL and steam CH again again2Cl2It is molten Liquid is configured to solution B.By solution B at 25 DEG C, mixed solution A is added with syringe pump in 1 hour.Stirring 3~12 hours, Reaction mixture is purified by column chromatography, obtains net product, is methyl (2S, 3S) -3- (3- shown in structure such as formula (i) Furans -2- base) -3- ((2- hydroxy phenyl) amino) -2- phenyl -2- propine amide methyl propionate, yield 60%, dr value is equal to > 95:5, HPLC purity are 98%.Compound shown in formula (i)1H NMR schematic diagram is as shown in figure 28,13C NMR schematic diagram is such as Shown in Figure 29, HPLC schematic diagram is as shown in figure 30.
1H NMR(400MHz,DMSO)δ9.45(s,1H),9.33(s,1H),7.52(s,1H),7.47–7.19(m,5H), 6.67 (d, J=7.5Hz, 1H), 6.60 (t, J=7.5Hz, 1H), 6.53-6.42 (m, 2H), 6.36 (m, 1H), 6.25 (d, J= 3.0Hz, 1H), 5.48 (d, J=9.7Hz, 1H), 5.40 (d, J=9.7Hz, 1H), 4.39 (s, 1H), 3.67 (s, 3H)13C NMR(100MHz,DMSO)δ169.61,151.69,151.47,144.39,142.39,135.84,135.40,127.63, 127.57,127.09,119.38,116.92,113.59,110.81,110.22,109.07,77.81,77.28,68.41, 56.74,52.64.HRMS(ESI):Calcd.for C23H20N2O5Na[M+Na]+:427.1270,Found:427.1258.
Embodiment 10
By imines (0.24mmol), rhodium acetate (0.0024mmol) andMolecular sieve (300mg) is mixed in 10mL single port bottle In, oil pump carries out nitrogen ventilation, and 1mL is added with 1mL syringe and steams CH again2Cl2Solution is configured to mixed solution A, at room temperature Stirring 10 minutes.Aryl diazo compound (0.2mmol) and amide compound (0.2mmol) are dissolved in 1mL and steam CH again again2Cl2It is molten Liquid is configured to solution B.By solution B at 25 DEG C, mixed solution A is added with syringe pump in 1 hour.Stirring 3~12 hours, Reaction mixture is purified by column chromatography, obtains net product, is methyl (2S, 3S) -3- (2- shown in structure such as formula (j) Methyl formate base) -3- ((2- hydroxy phenyl) amino) -2- phenyl -2- propine amide methyl propionate, yield 40%, dr value etc. In > 95:5, HPLC purity is 97%.Compound shown in formula (j)1H NMR schematic diagram is as shown in figure 31,13C NMR schematic diagram As shown in figure 32, HPLC schematic diagram is as shown in figure 33.
1H NMR (400MHz, DMSO) δ 9.95 (s, 1H), 9.31 (s, 1H), 7.59 (d, J=7.5Hz, 1H), 7.51- 7.41 (m, 1H), 7.33 (m, 2H), 7.24 (m, 5H), 6.60 (dd, J=14.5,7.6Hz, 2H), 6.40 (t, J=7.1Hz, 1H), 6.32 (m, 2H), 5.94 (d, J=8.7Hz, 1H), 4.35 (s, 1H), 3.63 (s, 3H), 3.54 (s, 3H)13C NMR (100MHz,DMSO)δ169.10,167.50,151.48,144.14,138.92,136.72,135.22,131.67,131.40, 129.14,128.23,127.58,127.30,119.35,116.31,113.25,111.11,77.74,77.34,68.48, 56.62,52.36,51.92.HRMS(ESI):Calcd.for C27H24N2O6Na[M+Na]+:495.1532,Found: 495.1535.
Embodiment 11
By imines (0.24mmol), rhodium acetate (0.0024mmol) andMolecular sieve (300mg) is mixed in 10mL single port bottle In, oil pump carries out nitrogen ventilation, and 1mL is added with 1mL syringe and steams CH again2Cl2Solution is configured to mixed solution A, at room temperature Stirring 10 minutes.Aryl diazo compound (0.2mmol) and amide compound (0.2mmol) are dissolved in 1mL and steam CH again again2Cl2It is molten Liquid is configured to solution B.By solution B at 25 DEG C, mixed solution A is added with syringe pump in 1 hour.Stirring 3~12 hours, Reaction mixture is purified by column chromatography, obtains net product, is methyl (2S, 3S) -3- (4- shown in structure such as formula (k) Bromophenyl) -3- ((2- hydroxy phenyl) amino) -2- (4- chlorphenyl) -2- propine amide methyl propionate, yield 70%, dr value Equal to > 95:5, HPLC purity is 95%.Compound shown in formula (k)1H NMR schematic diagram is as shown in figure 34,13C NMR signal As shown in figure 35, HPLC schematic diagram is as shown in figure 36 for figure.
1H NMR (400MHz, DMSO) δ 9.55 (s, 1H), 9.30 (s, 1H), 7.56-7.32 (m, 6H), 7.06 (d, J= 8.3Hz, 2H), 6.60 (d, J=7.4Hz, 1H), 6.45 (t, J=7.4Hz, 1H), 6.36 (t, J=7.3Hz, 1H), 6.22 (d, J=7.6Hz, 1H), 5.80 (d, J=8.2Hz, 1H), 5.29 (d, J=8.2Hz, 1H), 4.37 (s, 1H), 3.60 (s, 3H)13C NMR(100MHz,DMSO)δ169.09,151.77,144.33,137.59,135.80,135.09,132.46,130.65, 130.60,129.13,127.74,120.86,119.34,116.62,113.42,110.70,77.75,77.57,68.69, 61.56,52.82.HRMS(ESI):Calcd.for C25H20ClBrN2O4Na[M+Na]+:549.0194,Found: 549.0211.
Embodiment 12
By imines (0.24mmol), rhodium acetate (0.0024mmol) andMolecular sieve (300mg) is mixed in 10mL single port bottle In, oil pump carries out nitrogen ventilation, and 1mL is added with 1mL syringe and steams CH again2Cl2Solution is configured to mixed solution A, at room temperature Stirring 10 minutes.Aryl diazo compound (0.2mmol) and amide compound (0.2mmol) are dissolved in 1mL and steam CH again again2Cl2It is molten Liquid is configured to solution B.By solution B at 25 DEG C, mixed solution A is added with syringe pump in 1 hour.Stirring 3~12 hours, Reaction mixture is purified by column chromatography, obtains net product, is methyl (2S, 3S) -3- (4- shown in structure such as formula (l) Chlorphenyl) -3- ((2- hydroxy phenyl) amino) -2- (3- chlorphenyl) -2- propine amide methyl propionate, yield 88%, dr value Equal to 90:10, HPLC purity is 96%.Compound shown in formula (l)1H NMR schematic diagram is as shown in figure 37,13C NMR signal As shown in figure 38, HPLC schematic diagram is as shown in figure 39 for figure.
1H NMR (400MHz, MeOD) δ 7.31-7.15 (m, 6H), 7.09 (d, J=8.5Hz, 2H), 6.56-6.49 (d, J =7.1Hz, 1H), 6.43 (t, J=7.6Hz, 1H), 6.34 (t, J=7.1Hz, 1H), 6.20 (d, J=7.6Hz, 1H), 5.38 (s,1H),3.64(s,3H).13C NMR(100MHz,MeOD)δ170.96,154.44,145.97,139.73,138.50, 136.88,135.21,134.94,131.24,130.72,129.33,129.22,128.78,126.86,120.97,118.43, 114.70,112.29,71.64,63.65,54.04.HRMS(ESI):Calcd.for C25H21Cl2N2O4[M+H]+: 483.0878,Found:583.0879.
Embodiment 13
By imines (0.24mmol), rhodium acetate (0.0024mmol) andMolecular sieve (300mg) is mixed in 10mL single port bottle In, oil pump carries out nitrogen ventilation, and 1mL is added with 1mL syringe and steams CH again2Cl2Solution is configured to mixed solution A, at room temperature Stirring 10 minutes.Aryl diazo compound (0.2mmol) and amide compound (0.2mmol) are dissolved in 1mL and steam CH again again2Cl2It is molten Liquid is configured to solution B.By solution B at 25 DEG C, mixed solution A is added with syringe pump in 1 hour.Stirring 3~12 hours, Reaction mixture is purified by column chromatography, obtains net product, is methyl (2S, 3S) -3- (4- shown in structure such as formula (m) Chlorphenyl) -3- ((2- hydroxy phenyl) amino) -2- (4- chlorphenyl) -2- propine amide methyl propionate, yield 71%, dr value Equal to > 95:5, HPLC purity is 98%.Compound shown in formula (m)1H NMR schematic diagram is as shown in figure 40,13C NMR signal As shown in figure 41, HPLC schematic diagram is as shown in figure 42 for figure.
1H NMR (400MHz, MeOD) δ 7.28 (d, J=8.8Hz, 2H), 7.24-7.16 (m, 4H), 7.12 (d, J= 8.5Hz, 2H), 6.55-6.49 (m, 1H), 6.43 (dd, J=7.6,6.6Hz, 1H), 6.33 (t, J=7.5,6.5Hz, 1H), 6.19 (d, J=7.1Hz, 1H), 5.40 (3,1H), 3.63 (s, 3H)13C NMR(100MHz,MeOD)δ171.16,154.43, 145.91,138.71,136.96,136.22,135.13,134.91,131.21,130.15,129.39,129.36,120.99, 118.30,114.70,112.08,71.76,63.44,54.03.HRMS(ESI):Calcd.for C25H20Cl2N2O4Na[M+ Na]+:549.0194,Found:549.0211.
Embodiment 14
By imines (0.24mmol), rhodium acetate (0.0024mmol) andMolecular sieve (300mg) is mixed in 10mL single port bottle In, oil pump carries out nitrogen ventilation, and 1mL is added with 1mL syringe and steams CH again2Cl2Solution is configured to mixed solution A, at room temperature Stirring 10 minutes.Aryl diazo compound (0.2mmol) and amide compound (0.2mmol) are dissolved in 1mL and steam CH again again2Cl2It is molten Liquid is configured to solution B.By solution B at 25 DEG C, mixed solution A is added with syringe pump in 1 hour.Stirring 3~12 hours, Reaction mixture is purified by column chromatography, obtains net product, is methyl (2S, 3S) -2- third shown in structure such as formula (n) Acrylamide -3- (4- bromophenyl) -3- ((2- hydroxy phenyl) amino) -2 phenylpropionic acid methyl esters, yield 65%, dr value are equal to 85: 15, HPLC purity are 97%.Compound shown in formula (n)1H NMR schematic diagram is as shown in figure 43,13C NMR schematic diagram is as schemed Shown in 44, HPLC schematic diagram is as shown in figure 45.
1H NMR (400MHz, DMSO) δ 9.12 (s, 1H), 8.43 (s, 1H), 7.41 (d, J=15.1Hz, 2H), 7.30 (m, 5H), 7.08 (d, J=8.1Hz, 2H), 6.67 (dd, J=16.9,10.2Hz, 1H), 6.57 (d, J=7.4Hz, 1H), 6.46 (t, J=7.4Hz, 1H), 6.34 (t, J=7.1Hz, 2H), 6.23 (d, J=7.7Hz, 1H), 6.11 (d, J=16.9Hz, 1H), 5.68 (d, J=10.5Hz, 1H), 5.57 (d, J=7.0Hz, 1H), 3.61 (s, 3H)13C NMR(100MHz,DMSO)δ 170.43,165.20,144.20,138.70,136.64,135.68,131.15,130.70,130.51,127.98,127.67, 126.95,129.90,120.69,119.33,116.00,113.27,109.83,69.39,60.63,52.96.HRMS(ESI): Calcd.for C25H23BrN2O4[M+Na]+:517.0739,Found:517.0717.
Embodiment 15
By imines (0.24mmol), rhodium acetate (0.0024mmol) andMolecular sieve (300mg) is mixed in 10mL single port bottle In, oil pump carries out nitrogen ventilation, and 1mL is added with 1mL syringe and steams CH again2Cl2Solution is configured to mixed solution A, at room temperature Stirring 10 minutes.Aryl diazo compound (0.2mmol) and amide compound (0.2mmol) are dissolved in 1mL and steam CH again again2Cl2It is molten Liquid is configured to solution B.By solution B at 25 DEG C, mixed solution A is added with syringe pump in 1 hour.Stirring 3~12 hours, Reaction mixture is purified by column chromatography, obtains net product, is methyl (2S, 3S) -2- second shown in structure such as formula (o) Acylamino- -3- (4- bromophenyl) -3- ((2- hydroxy phenyl) amino) -2- phenylpropionic acid methyl ester, yield 77%, dr value are equal to 80:20, HPLC purity are 98%.Compound shown in formula (o)1H NMR schematic diagram is as shown in figure 46,13C NMR schematic diagram is such as Shown in Figure 47, HPLC schematic diagram is as shown in figure 48.
1H NMR (400MHz, DMSO) δ 9.08 (s, 1H), 8.18 (s, 1H), 7.45 (d, J=8.4Hz, 2H), 7.35- 7.25 (m, 5H), 7.11 (d, J=8.4Hz, 2H), 6.56 (dd, J=7.6,1.2Hz, 1H), 6.45 (m, 1H), 6.37-6.28 (m, 1H), 6.22 (m, 2H), 5.52 (d, J=7.4Hz, 1H), 3.59 (s, 3H), 1.99 (s, 3H)13C NMR(100MHz, DMSO)δ170.63,170.36,144.20,138.88,136.80,135.73,130.67,130.56,127.91,127.60, 126.99,120.60,119.33,115.92,113.27,109.82,69.16,60.48,52.83,22.93.HRMS(ESI): Calcd.for C24H23BrN2O4Na[M+Na]+:505.0739,Found:505.0716.
The test of 16 anti-tumor activity of embodiment
IC50Value test
Human colon carcinoma HCT116 cell, human liver cancer BEL7402 cell, human liver cancer SMMC7721 cell are inoculated in respectively In McCoy, s5A culture solution (10% serum, 1% blueness-streptomysin) and 1640 culture medium.37 DEG C are placed in, 5%CO2In incubator, Passage in every 2-3 days is primary, tests logarithmic growth phase cell.CCK-8 method measures IC50Value.
Logarithmic growth phase cell takes with configured fresh medium adjustment cell suspension to 2500~4000/ml 100ul (2,000 cells/well) cell suspension inoculation is to 96 well culture plates.It is placed in 5%CO2, is incubated overnight culture in 37 DEG C of incubators Afterwards, fresh cell medium is replaced, 200ul DMSO is added in every hole, and diluted concentration gradient drug is incubated for altogether with cell in equal volume 72h, replaces fresh cell medium, and every hole adds 100ul+10ulCCK-8 solution to continue to be incubated for 1-4 hour, terminates and cultivate, with more Function microplate reader (Molecular Devices M5) detects the absorbance of 450nm, and the absorbance correction cell number of 620nm is poor It is different.
Untested compound (1~embodiment of embodiment 15) is dissolved in DMSO, and with further being diluted in culture solution. DMSO ultimate density is no more than 0.1% (v/v).Control group is the tumour cell that isometric DMSO is added；Blank group is cell-free, It is added in culture solution and isometric DMSO is added.In primary experiment, each experiment condition is all provided with 3 multiple holes.Calculate each concentration Compounds on cell growth inhibiting rate, calculation formula are as follows: inhibiting rate (%)={ 1- [(dosing group)-(blank group)]/[(right According to group)-(blank group)] x 100%, IC is calculated with GraphPad Prim650(for control group is down in cell growth Drug concentration needed for 50%).Its testing result such as the following table 1.
Table one: one kind-α containing alpha-aromatic, β of the invention-diamino acid ester derivant biologically active data
" --- " indicates inactive；aIndicate inhibiting rate (%) of the positive drug in tumour cell.
To sum up, the experimental results showed that ,-the α containing alpha-aromatic, β-diamino acid ester derivant are to human colon cancer cell, human liver cancer Cell all has significant inhibiting effect.Compared with Example 4, embodiment 14 and embodiment 15 are inactive, illustrate alkynyl be must It must functional group；6 activity of embodiment reduces, and illustrates that heterocycle is unfavorable group.In general ,-the α containing alpha-aromatic, β-diamino acid esters Derivative shows excellent anticancer activity, and anticancer activity is at 1.354~6.80 μM；With the taxol medicine reported in the market (PTX) it compares, cell activity is quite even better, very likely develops patent medicine or potential medicine, while this also illustrates such Compound has very good inhibitor against colon carcinoma cells, resisting liver cancer activity.The present invention provides for exploitation treatment colon cancer, liver-cancer medicine Very bright development prospect.

Claims (3)

1.-the α containing alpha-aromatic as shown in formula (I), β-diamino acid ester derivant application in preparation of anti-tumor drugs, feature It is, formula (I) structure are as follows:
Wherein,
Ar is aryl, phenyl, the methoxy-substituted phenyl, fluoroform that phenyl, the nitro replaced selected from phenyl, halogen replaces Phenyl, the alkyl-substituted phenyl of C1-C10 of base substitution；
R1For hydrogen, C1-C10 alkyl, phenyl, the alkyl-substituted phenyl of C1-C10, benzyl；
R2For alkynyl；
R3For with halogen, C1-C10 alkyl, nitro, methoxyl group, trifluoromethyl, ester group phenyl ring, furan nucleus, thiphene ring, pyrroles Ring, 2- methyl benzoate base.
2. application as described in claim 1, which is characterized in that the tumour is colon cancer, liver cancer.
3. application as claimed in claim 2, which is characterized in that the colon cancer includes colon cancer HCT116 cell；The liver Cancer includes liver cancer BEL7402 cell, liver cancer SMMC7721 cell.
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