CN102731332B - Synthetic method of alpha-chiral amino acid derivatives - Google Patents

Synthetic method of alpha-chiral amino acid derivatives Download PDF

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CN102731332B
CN102731332B CN201210183833.7A CN201210183833A CN102731332B CN 102731332 B CN102731332 B CN 102731332B CN 201210183833 A CN201210183833 A CN 201210183833A CN 102731332 B CN102731332 B CN 102731332B
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amino acid
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chiral
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CN102731332A (en
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曾伟
陈嘉燕
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South China University of Technology SCUT
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Abstract

The invention discloses a synthetic method of alpha-chiral amino acid derivatives. The method comprises the following steps: taking an imine, mixing the imine with arylboronic acid, and reacting for 24-48h at 0-90DEG C in the presence of a palladium salt, a chiral ligand and a solvent to form the alpha-chiral amino acid derivatives, wherein the molar ratio of the imine to the aryl boric acid is 1:(1-5), and the chiral ligand is an oxazoline ligand. The method of the invention has the advantages of simplicity, high efficiency, cheap, easily available and nontoxic raw materials, insensitivity to water and air in the reaction process, and high enantioselectivity, wherein the highest enantioselectivity can reach 98%. Additionally, the operation process of above whole experiment is simple and is easy to implement, the steps are simple, and the products are easy to purify.

Description

The synthetic method of alpha-chiral amino acid derivative
Technical field
The present invention relates to the synthetic method of alpha-chiral amino acid derivative.
Background technology
Amino acid is not only the basic comprising unit of protein, its derivative or the important structure unit of a lot of natural product and drug molecule.Chiral amino acid and derivative thereof have important use at biomedicine field, the synthetic precursor of chiral amino acid or many chiral catalysts, so the method for asymmetric synthesis of a-amino acid and derivative thereof is paid attention to always widely.
The chiralα-aminoacid of report and the synthetic method of derivative thereof mainly contain at present: the one, and by going back original reagent, imines is carried out to hydrogenization under certain condition and obtained target product.As (1) usings H2 as going back original reagent (Shang, Gao.; Yang, Q.; Zhang, X.M.Rh-Catalyzed Asymmetric Hydrogenation of a-Aryl Imino Esters:An Efficient Enantioselective Synthesis of Aryl Glycine Derivatives.[J] Angew.Chem.Int.Ed.2006,45,6360.; Wang, Y.Q.; Lu, S.M.; Zhou, Y.G.Highly Enantioselective Pd-Catalyzed Asymmetric Hydrogenation of Activated Imines.[J] J.Org.Chem.2007,72,3729); (2) using Hantzsch ester as going back original reagent (Kang, Q.; Zhao, Z.A.; You, S.L.Highly Enantioselective Transfer Hydrogenation of a-Imino Esters by a Phosphoric Acid.[J] Adv.Synth.Catal.2007,349,1657.; Li, G.L.; Liang, Y.X.; Antilla, J.C.A Vaulted Biaryl Phosphoric Acid-Catalyzed Reduction of r-Imino Esters:The Highly Enantioselective Preparation of r-Amino Esters.[J] J.Am.Chem.Soc.2007,129,5830); (3) using other reagent as reductive agent (Zhu, C.; Akiyama, T.Enantioselective Organocatalytic Transfer Hydrogenation of a-Imino Esters by Utilization of Benzothiazoline as Highly EfficientReducing Agent.[J] Adv.Synth.Catal.2010,352,1846).
The 2nd, by alkylating reagent, thereby under certain conditions imines is carried out to addition, obtain target product.As (1) organoaluminum reagent (Niwa, Y.; Shimizu, M.Tandem N-Alkylation-C-Allylation Reaction of r-Imino Esters with Organoaluminums and Allyltributyltin.[J] J.Am.Chem.Soc.2003,125,3720); (2) organic zinc reagent (Fu, P.; Snapper, M.L.; Hoveyda, A.H.Catalytic Asymmetric Alkylations of Ketoimines.Enantioselective Synthesis of N-Substituted Quaternary Carbon Stereogenic Centers by Zr-Catalyzed Additions of Dialkylzinc Reagents to Aryl-, Alkyl-, and Trifluoroalkyl-Substituted Ketoimines.[J] J.Am.Chem.Soc.2008,130,5530).
Summary of the invention
In order to overcome the shortcoming and deficiency of prior art, the object of the present invention is to provide a kind of synthetic method of easy, efficient alpha-chiral amino acid derivative, the method raw material used is cheap and easy to get and nontoxic, and whole operating process is simple.
Object of the present invention is achieved through the following technical solutions:
The synthetic method of alpha-chiral amino acid derivative, comprises the following steps:
Get imines and mix with aryl boric acid, under palladium salt, chiral ligand and solvent exist, at 0-90 ℃, react 24 ~ 48h, generate alpha-chiral amino acid derivative;
After reaction finishes, adopt column chromatography by product separation purifying; The elutriant of described column chromatography is the mixed solvent of sherwood oil and ethyl acetate;
The structure of described imines is suc as formula shown in A, and the structure of described aryl boric acid is suc as formula shown in B, and the structure of described alpha-chiral amino acid derivative is suc as formula shown in C;
In formula A and formula C, R is 4-OMeC 6h 4, 4-ClC 6h 4, 4-BrC 6h 4, 4-NO 2c 6h 4, 4-MeC 6h 4, Ph or 3-COOEtC 6h 4in a kind of; In formula B and formula C, Ar is Ph, 4-MeC 6h 4, 4-OMeC 6h 4, 4-ClC 6h 4, 4-FC 6h 4, 4-CF 3c 6h 4, 4-xenyl, 1-naphthyl, 3-MeC 6h 4, 3-ClC 6h 4, 3-OMeC 6h 4, a kind of in 3-thienyl, 2-thienyl or 3-furyl;
Synthetic method existing bibliographical information (Borrione, the E. of described imines (formula A); Prato, M.; Scorrano, G.; Stivanello, M.Synthesis and cycloaddition reactions of ethyl glyoxylate imines.Synthesis of substituted furo-[3,2-c] quinolines and 7H-indeno[2,1-c] quinolines.[J] J.Heterocycl.Chem.1988,25,1831);
The mol ratio of described imines and aryl boric acid is 1:(1 ~ 5), preferred 1:1;
The mol ratio of described chiral ligand and aryl boric acid is 1:10;
Described palladium salt is a kind of in palladium chloride, palladium, trifluoracetic acid palladium, dichloro diacetonitrile palladium or dichloro two triphenyl phosphorus palladiums, preferably trifluoracetic acid palladium;
(L*) is oxazoline ligand to described chiral ligand, preferred (S, S)-2, 2 '-methylene-bis (4-phenyl-2-oxazoline), (S, S)-2, 2 '-isopropylidene two (2-oxazoline), (S, S)-4, 4 '-di-isopropyl-2, 2 '-bis-(2-oxazolines), (S, S)-4, 4 '-phenylbenzene-2, 2 '-bis-(2-oxazolines), (S, S)-4, 4 '-dibenzyl-2, 2 '-bis-(2-oxazolines), (S)-2-(4-benzyl) oxazoline-pyridine, (S)-2-(4-phenyl) oxazoline-pyridine or (S)-2-(a kind of in 4-sec.-propyl) oxazoline-pyridine, (S)-2-(4-phenyl) oxazoline-pyridine particularly preferably,
Described solvent is DMF or Nitromethane 99Min..
The reaction occurring in said process is as follows:
The present invention has following advantage and effect with respect to prior art:
Method of the present invention is easy, efficient, and raw material used is cheap and easy to get and nontoxic, and this preparation method is insensitive to water and air in reaction process, and enantioselectivity is high, and high energy reaches 98%.Whole experimental implementation process is simple in addition, and step is easy, the easy purifying of product.
Accompanying drawing explanation
Fig. 1 is the hydrogen spectrogram of compound 1.
Fig. 2 is the carbon spectrogram of compound 1.
Fig. 3 is the hydrogen spectrogram of compound 2.
Fig. 4 is the carbon spectrogram of compound 2.
Fig. 5 is the hydrogen spectrogram of compound 3.
Fig. 6 is the carbon spectrogram of compound 3.
Fig. 7 is the hydrogen spectrogram of compound 4.
Fig. 8 is the carbon spectrogram of compound 4.
Fig. 9 is the hydrogen spectrogram of compound 5.
Figure 10 is the carbon spectrogram of compound 5.
Figure 11 is racemic compound 1 high performance liquid chromatography separation graph.
Figure 12 is chipal compounds 1 high performance liquid chromatography separation graph.
Figure 13 is racemic compound 2 high performance liquid chromatography separation graph.
Figure 14 is chipal compounds 2 high performance liquid chromatography separation graph.
Figure 15 is racemic compound 3 high performance liquid chromatography separation graph.
Figure 16 is chipal compounds 3 high performance liquid chromatography separation graph.
Figure 17 is racemic compound 4 high performance liquid chromatography separation graph.
Figure 18 is chipal compounds 4 high performance liquid chromatography separation graph.
Figure 19 is racemic compound 5 high performance liquid chromatography separation graph.
Figure 20 is chipal compounds 5 high performance liquid chromatography separation graph.
Embodiment
Below in conjunction with embodiment and accompanying drawing, the present invention is described in further detail, but embodiments of the present invention are not limited to this.
Embodiment 1
The synthetic method of alpha-chiral amino acid derivative, comprises the following steps:
(1) in sealed tube, add P-nethoxyaniline (13.8mg, 0.1mmol), glyoxylic acid ethyl ester (10.2mg, 0.1mmol), sodium sulfate (71mg, 0.5mmol), methylene dichloride (2mL), mixed solution is stirring reaction 0.5h at room temperature.Then remove by filter sodium sulfate, use washed with dichloromethane filter residue, be spin-dried for methylene chloride, obtain imines.
(2) in sealed tube, add the imines (20.7mg of step (1), 0.1mmol), phenylo boric acid (12.2mg, 0.1mmol), trifluoracetic acid palladium (4, .2mg, 0.01mmol), (S)-2-(4-phenyl) oxazoline-pyridine (2.3mg, 0.01mmol), Nitromethane 99Min. (2mL), mixed solution reacts 24h under 50 ℃ of conditions.After completion of the reaction, after question response system cool to room temperature, filter, be spin-dried for, adopt the further separation and purification of column chromatography, obtain product 23mg, productive rate is: 81%, ee value: 95%.
The structural characterization data of the resulting product of the present embodiment are as follows:
1h NMR (400MHz, CDCl 3) δ (ppm) 7.49 (d, J=7.5Hz, 2H), 7.36-7.30 (m, 3H), 6.72 (d, J=8.8Hz, 2H), 6.53 (d, J=8.7Hz, 2H), 5.00 (s, 1H), 4.67 (s, 1H), 4.25-4.11 (m, 2H), 3.70 (s, 3H), 1.20 (t, J=7.1Hz, 3H) .(is shown in Fig. 1)
13c NMR (100MHz, CDCl 3) δ (ppm) 172.1,152.5,140.3,137.9,128.8,128.2,127.3,114.8,61.7,61.7,55.7,14.1.(is shown in Fig. 2)
MS m/z(M +),286.6,274.7,230.7,199.4,146.4,102.5,60.6.
As follows according to the structure of above inferred from input data embodiment 1 products obtained therefrom:
Compound 1[α] d 20=+66.0 o(c=0.1, CHCl 3), compare with the specific rotation of known references and show that the absolute configuration of this compound is S configuration.
Compound 1 is carried out to high performance liquid chromatography separation, high performance liquid chromatography separation condition: chirality AD-H post, Virahol: 0.05mL/min, normal hexane: 0.5mL/min.The results are shown in Figure 11-12, show 1-2(table 1 for racemic compound 1 high performance liquid chromatography separation graph data, table 2 is chipal compounds 1 high performance liquid chromatography separation graph data):
Table 1
Peak # Retention time Area Highly Area % Height %
1 3.973 44120 1989 0.307 0.397
2 6.010 73844 4566 0.514 0.911
3 8.445 303072 15911 2.109 3.174
4 15.175 6956036 246307 48.409 49.129
5 16.381 6992263 232577 48.661 46.390
Amount to 14369335 501349 100.000 100.000
Table 2
Peak # Retention time Area Highly Area % Height %
1 3.691 16824 2061 0.210 0.756
2 3.985 43454 1938 0.543 0.711
3 6.005 17971 1174 0.225 0.430
4 8.454 168811 8694 2.110 3.189
5 15.143 213133 7619 2.664 2.794
6 16.342 7540544 251165 94.248 92.120
Amount to 8000738 272650 100.000 100.000
By Figure 11-12, table 1-2, can be found out: compound 1 ee=95%[λ=254nm, t (small peak)=15.14min, t (large peak)=16.34min].
Embodiment 2
The synthetic method of alpha-chiral amino acid derivative, comprises the following steps:
(1) in sealed tube, add p-Chlorobenzoic acid amide (12.7mg, 0.1mmol), glyoxylic acid ethyl ester (10.2mg, 0.1mmol), sodium sulfate (71mg, 0.5mmol), methylene dichloride (2mL), mixed solution is stirring reaction 0.5h at room temperature.Then remove by filter sodium sulfate, use washed with dichloromethane filter residue, be spin-dried for methylene chloride, obtain imines.
(2) in sealed tube, add the imines (20.7mg of step (1), 0.1mmol), phenylo boric acid (12.2mg, 0.1mmol), trifluoracetic acid palladium (4.2mg, 0.01mmol), (S)-2-(4-phenyl) oxazoline-pyridine (2.3mg, 0.01mmol), Nitromethane 99Min. (2mL), mixed solution reacts 24h under 50 ℃ of conditions.After completion of the reaction, after question response system cool to room temperature, filter, be spin-dried for, adopt the further separation and purification of column chromatography, obtain product 27mg, productive rate is: 93%, ee value: 96%.
The structural characterization data of the resulting product of the present embodiment are as follows:
1h NMR (400MHz, CDCl 3) δ (ppm) 7.51-7.48 (m, 2H), 7.37-7.30 (m, 3H), 7.09-7.05 (m, 2H), 6.51-6.47 (m, 2H), 5.06-5.03 (m, 2H), 4.29-4.11 (m, 2H), 1.23 (t, J=8.0,4.0Hz, 3H) .(is shown in Fig. 3)
13c NMR (100MHz, CDCl 3) δ (ppm) 171.6,144.5,137.3,129.0,128.4,127.2,122.7,114.5,62.0,60.8,14.1.(is shown in Fig. 4)
MS m/z(M +),290.5,274.7,230.6,163.4,100.5,88.4.
As follows according to the structure of above inferred from input data products obtained therefrom:
Compound 2[α] d 20=+97.5 o(c=0.2, CHCl 3), compare and show that the absolute configuration of this compound is S configuration with the specific rotation of known document.
Compound 2 is carried out to high performance liquid chromatography separation, high performance liquid chromatography separation condition: chirality Lux 5uCellulose-1 post, Virahol: 0.1mL/min, normal hexane: 0.4mL/min.The results are shown in Figure 13-14, show 3-4(table 3 for racemic compound 2 high performance liquid chromatography separation graph data, table 4 is chipal compounds 2 high performance liquid chromatography separation graph data):
Table 3
Peak # Retention time Area Highly Area % Height %
1 6.103 28849 1157 0.033 0.026
2 8.139 41362 2170 0.047 0.049
3 9.921 43309542 2299701 49.180 52.131
4 11.118 44397332 2098289 50.416 47.565
5 12.646 285711 10084 0.324 0.229
Amount to 88062796 4411405 100.000 100.000
Table 4
Peak # Retention time Area Highly Area % Height %
1 5.953 31088 926 0.680 0.416
2 8.139 30098 1336 0.658 0.600
3 9.936 82464 4259 1.804 1.914
4 11.152 4317818 212501 94.447 95.504
5 12.703 66835 2126 1.462 0.955
6 14.271 43398 1357 0.949 0.610
Amount to 4571700 222504 100.000 100.000
By Figure 13-14, table 3-4, can be found out: compound 2ee=96%[λ=254nm, t (small peak)=9.94min, t (large peak)=11.15min].
Embodiment 3
The synthetic method of alpha-chiral amino acid derivative, comprises the following steps:
(1) in sealed tube, add aniline (9.3mg, 0.1mmol), glyoxylic acid ethyl ester (10.2mg, 0.1mmol), sodium sulfate (71mg, 0.5mmol), methylene dichloride (2mL), mixed solution is stirring reaction 0.5h at room temperature.Then remove by filter sodium sulfate, use washed with dichloromethane filter residue, be spin-dried for methylene chloride, obtain imines.
(2) in sealed tube, add the imines (20.7mg of step (1), 0.1mmol), phenylo boric acid (12.2mg, 0.1mmol), trifluoracetic acid palladium (4.2mg, 0.01mmol), (S)-2-(4-phenyl) oxazoline-pyridine (2.3mg, 0.01mmol), Nitromethane 99Min. (2mL), mixed solution reacts 24h under 50 ℃ of conditions.After completion of the reaction, after question response system cool to room temperature, filter, be spin-dried for, adopt the further separation and purification of column chromatography, obtain product 14mg, productive rate is: 55%, ee value: 96%.
The structural characterization data of the present embodiment products obtained therefrom are as follows:
1h NMR (400MHz, CDCl 3) δ (ppm) 7.50 (d, J=7.7Hz, 2H), 7.37-7.26 (m, 3H), 7.11 (t, J=7.7Hz, 2H), 6.73-6.70 (m, 1H), 6.56 (d, J=8.4Hz, 2H), 5.06 (d, J=5.6Hz, 1H), 4.96 (s, 1H), 4.29-4.11 (m, 2H), 1.23 (t, J=12.0Hz, 8.0Hz, 3H) .(is shown in Fig. 5)
13c NMR (101MHz, CDCl 3) δ (ppm) 171.9,146.0,137.8,129.3,128.8,128.2,127.2,118.1,113.4,61.8,60.8,14.1.(is shown in Fig. 6)
MS m/z(M +),256.5,230.6,182.5,102.5,60.6.
As follows according to the structure of above inferred from input data products obtained therefrom:
Compound 3[α] d 20+ 107.7 o(c=0.22, CHCl 3), compare and show that the absolute configuration of this compound is S configuration with the specific rotation of known document.
Compound 3 is carried out to high performance liquid chromatography separation, high performance liquid chromatography separation condition: chirality OD-H post, Virahol: 0.01mL/min, normal hexane: 0.35mL/min.The results are shown in Figure 15-16, show 5-6(table 5 for racemic compound 3 high performance liquid chromatography separation graph data, table 6 is chipal compounds 3 high performance liquid chromatography separation graph data):
Table 5
Peak # Retention time Area Highly Area % Height %
1 5.913 202859 8405 3.145 5.485
2 8.152 424464 7034 6.581 4.591
3 14.590 29388 374 0.456 0.244
4 15.990 2891281 72750 44.830 47.477
5 18.205 2901430 64669 44.987 42.203
Amount to 6449422 153232 100.000 100.000
Table 6
Peak # Retention time Area Highly Area % Height %
1 5.920 303724 10736 4.520 6.214
2 9.123 36816 640 0.548 0.371
3 10.022 56949 2078 0.847 1.202
4 10.559 21434 690 0.319 0.399
5 16.025 6189691 156311 92.107 90.468
6 18.420 111527 2327 1.660 1.347
Amount to 6720140 17281 100.000 100.000
By Figure 15-16, table 5-6, can be found out: compound 3 ee=96%[λ=254nm, t (small peak)=18.42min, t (large peak)=16.03min].
Embodiment 4
The synthetic method of alpha-chiral amino acid derivative, comprises the following steps:
(1) in sealed tube, add P-nethoxyaniline (13.8mg, 0.1mmol), glyoxylic acid ethyl ester (10.2mg, 0.1mmol), sodium sulfate (71mg, 0.5mmol), methylene dichloride (2mL), mixed solution is stirring reaction 0.5h at room temperature.Then remove by filter sodium sulfate, use washed with dichloromethane filter residue, be spin-dried for methylene chloride, obtain imines.
(2) in sealed tube, add the imines (20.7mg of step (1), 0.1mmol), to methylphenylboronic acid (13.6mg, 0.1mmol), trifluoracetic acid palladium (4.2mg, 0.01mmol), (S)-2-(4-phenyl) oxazoline-pyridine (2.3mg, 0.01mmol), Nitromethane 99Min. (2mL), mixed solution reacts 24h under 50 ℃ of conditions.After completion of the reaction, after question response system cool to room temperature, filter, be spin-dried for, adopt the further separation and purification of column chromatography, obtain product 17mg, productive rate is: 57%, ee value: 90%.
The structural characterization data of the present embodiment products obtained therefrom are as follows:
1h NMR (400MHz, CDCl 3) δ (ppm) 7.38 (d, J=7.8Hz, 2H), 7.16 (d, J=7.8Hz, 2H), 6.73 (d, J=8.7Hz, 2H), 6.55 (d, J=8.7Hz, 2H), 4.98 (s, 1H), 4.65 (s, 1H), 4.25-4.11 (m, 2H), 3.71 (s, 3H), 2.34 (s, 3H), 1.22 (t, J=7.1Hz, 3H) .(is shown in Fig. 7)
13c NMR (100MHz, CDCl 3) δ (ppm) 172.2,152.4,140.4,137.9,134.9,129.5,127.1,114.8,114.7,61.6,61.4,55.7,21.2,14.1.(is shown in Fig. 8)
MS m/z(M +),300.6,274.7,218.6,194.4,124.4,102.5.
As follows according to the structure of above inferred from input data products obtained therefrom:
Compound 4[α] d 20=+87.5 o(c=0.2, CHCl 3), compare and show that the absolute configuration of this compound is S configuration with the specific rotation of known document.
Compound 4 is carried out to high performance liquid chromatography separation, high performance liquid chromatography separation condition: chirality AD-H post, Virahol: 0.01mL/min, normal hexane: 0.35mL/min.The results are shown in Figure 17-18, show 7-8(table 7 for racemic compound 4 high performance liquid chromatography separation graph data, table 8 is chipal compounds 4 high performance liquid chromatography separation graph data):
Table 7
Peak # Retention time Area Highly Area % Height %
1 33.839 9070710 132656 49.732 50.355
2 36.256 9168321 130784 50.268 49.645
Amount to 18239031 263440 100.000 100.000
Table 8
Peak # Retention time Area Highly Area % Height %
1 10.123 457155 14556 1.665 2.909
2 11.998 5835349 160330 21.249 32.038
3 22.964 1454608 29598 5.297 5.915
4 33.825 951617 14792 3.465 2.956
5 36.174 18762601 281153 68.324 56.182
Amount to 27461331 500430 100.000 100.000
By Figure 17-18, table 7-8, can be found out: compound 4 ee=90%, [λ=254nm, t (small peak)=33.83min, t (large peak)=36.17min].
Embodiment 5
The synthetic method of alpha-chiral amino acid derivative, comprises the following steps:
(1) in sealed tube, add P-nethoxyaniline (13.8mg, 0.1mmol), glyoxylic acid ethyl ester (10.2mg, 0.1mmol), sodium sulfate (71mg, 0.5mmol), methylene dichloride (2mL), mixed solution is stirring reaction 0.5h at room temperature.Then remove by filter sodium sulfate, use washed with dichloromethane filter residue, be spin-dried for methylene chloride, obtain imines.
(2) in sealed tube, add the imines (20.7mg of step (1), 0.1mmol), 3-thiophene phenylo boric acid (12.8mg, 0.1mmol), trifluoracetic acid palladium (4.2mg, 0.01mmol), (S)-2-(4-phenyl) oxazoline-pyridine (2.3mg, 0.01mmol), Nitromethane 99Min. (2mL), mixed solution reacts 24h under 50 ℃ of conditions.After completion of the reaction, after question response system cool to room temperature, filter, be spin-dried for, adopt the further separation and purification of column chromatography, obtain product 18mg, productive rate is: 62%, ee value: 93%.
The structural characterization data of the present embodiment products obtained therefrom are as follows:
1h NMR (400MHz, CDCl 3) δ (ppm) 7.41-7.22 (m, 2H), 7.17 (d, J=4.9Hz, 1H), 6.76 (d, J=8.8Hz, 2H), 6.59 (d, J=8.8Hz, 2H), 5.13 (s, 1H), 4.26-4.16 (s, 1H), 4.21 (m, 2H), 3.73 (s, 3H), 1.25 (t, J=7.2Hz, 3H) .(is shown in Fig. 9)
13c NMR (100MHz, CDCl 3) δ 171.8,152.7,140.4,138.5,126.5,126.3,122.8,115.0,114.9,61.7,58.1,55.7,14.1.(is shown in Figure 10)
MS m/z(M +),314.3,274.5,229.3,218.3,169.3,123.4,97.4.
As follows according to the structure of above inferred from input data products obtained therefrom:
Compound 5[α] d 20=+23.5 o(c=0.2, CHCl 3), compare and show that the absolute configuration of this compound is S configuration with the specific rotation of known document.
Compound 5 is carried out to high performance liquid chromatography separation, high performance liquid chromatography separation condition: chirality AD-H post, Virahol: 0.01mL/min, normal hexane: 0.35mL/min.The results are shown in Figure 19-20, show 9-10(table 9 for racemic compound 5 high performance liquid chromatography separation graph data, table 10 is chipal compounds 5 high performance liquid chromatography separation graph data):
Table 9
Peak # Retention time Area Highly Area % Height %
1 47.038 28823123 353439 50.334 53.994
2 53.247 28440917 301149 49.666 46.006
Amount to 57264040 654588 100.000 100.000
Table 10
Peak # Retention time Area Highly Area % Height %
1 5.525 7675 585 0.124 0.785
2 6.213 276602 6700 4.468 8.990
3 20.311 447045 9344 7.218 12.539
4 46.244 291105 2560 4.700 3.435
5 53.300 5170771 55331 83.490 74.251
Amount to 6193287 74519 100.000 100.000
By Figure 19-20, table 9-10, can be found out: compound 5 ee=93%, [λ=254nm, t (small peak)=46.24min, t (large peak)=53.30min].
Above-described embodiment is preferably embodiment of the present invention; but embodiments of the present invention are not restricted to the described embodiments; other any do not deviate from change, the modification done under spirit of the present invention and principle, substitutes, combination, simplify; all should be equivalent substitute mode, within being included in protection scope of the present invention.

Claims (9)

1. the synthetic method of alpha-chiral amino acid derivative, is characterized in that comprising the following steps:
Get imines and mix with aryl boric acid, under palladium salt, chiral ligand and solvent exist, at 0-90 ℃, react 24～48h, generate alpha-chiral amino acid derivative;
The structure of described imines is suc as formula shown in A, and the structure of described aryl boric acid is suc as formula shown in B, and the structure of described alpha-chiral amino acid derivative is suc as formula shown in C;
In formula A and formula C, R is 4-OMeC 6h 4, 4-ClC 6h 4or a kind of in Ph; In formula B and formula C, Ar is Ph or 4-MeC 6h 4;
The mol ratio of described imines and aryl boric acid is 1:(1～5);
Described chiral ligand is oxazoline ligand.
2. the synthetic method of alpha-chiral amino acid derivative according to claim 1, is characterized in that: after reaction finishes, adopt column chromatography by product separation purifying; The elutriant of described column chromatography is the mixed solvent of sherwood oil and ethyl acetate.
3. the synthetic method of alpha-chiral amino acid derivative according to claim 1, is characterized in that: the mol ratio of described imines and aryl boric acid is 1:1.
4. the synthetic method of alpha-chiral amino acid derivative according to claim 1, is characterized in that: the mol ratio of described chiral ligand and aryl boric acid is 1:10.
5. the synthetic method of alpha-chiral amino acid derivative according to claim 1, is characterized in that: described palladium salt is a kind of in palladium chloride, palladium, trifluoracetic acid palladium, dichloro diacetonitrile palladium or dichloro two triphenyl phosphorus palladiums.
6. the synthetic method of alpha-chiral amino acid derivative according to claim 1, is characterized in that: described palladium salt is trifluoracetic acid palladium.
7. the synthetic method of alpha-chiral amino acid derivative according to claim 1, it is characterized in that: described chiral ligand is (S, S)-2, 2 '-methylene-bis (4-phenyl-2-oxazoline), (S, S)-2, 2 '-isopropylidene two (2-oxazoline), (S, S)-4, 4 '-di-isopropyl-2, 2 '-bis-(2-oxazolines), (S, S)-4, 4 '-phenylbenzene-2, 2 '-bis-(2-oxazolines), (S, S)-4, 4 '-dibenzyl-2, 2 '-bis-(2-oxazolines), (S)-2-(4-benzyl) oxazoline-pyridine, (S)-2-(4-phenyl) oxazoline-pyridine or (S)-2-(a kind of in 4-sec.-propyl) oxazoline-pyridine.
8. the synthetic method of alpha-chiral amino acid derivative according to claim 1, is characterized in that: described chiral ligand is (S)-2-(4-phenyl) oxazoline-pyridine.
9. the synthetic method of alpha-chiral amino acid derivative according to claim 1, is characterized in that: described solvent is DMF or Nitromethane 99Min..
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