CN112279743B - Synthesis method of chiral alpha-amino acid ester derivative - Google Patents
Synthesis method of chiral alpha-amino acid ester derivative Download PDFInfo
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Abstract
The invention discloses a method for synthesizing chiral alpha-amino acid ester derivatives, which comprises the following steps: the chiral alpha-amino acid ester derivative is prepared by catalyzing asymmetric hydrogenation of imido ester by taking a complex prepared in situ by reacting a chiral ferrocene skeleton phosphine-phosphoramidite ligand with a metal iridium precursor as a catalyst. Provides a feasible way for synthesizing amino acid. Compared with other methods for synthesizing chiral amino acid ester, the method for synthesizing the hydrogenated chiral ferrocene skeleton phosphine-phosphoramidite ligand is simple, low in price and suitable for kilogram-level production, the iridium/chiral ferrocene skeleton phosphine-phosphoramidite system is high in catalytic activity and enantioselectivity, the enantiomeric excess (ee value) of the product is up to more than 96%, the hydrogenation reaction is simple to operate, mild in condition and high in atom economy, and the method is suitable for industrial production, has a good result on the synthesis of phenylglycine ethyl ester, achieves the yield of 92% and the enantioselectivity of 91%, and has good industrial practicability.
Description
Technical Field
The invention belongs to the field of organic synthesis, and particularly relates to a synthesis method of a chiral alpha-amino acid ester derivative, which is suitable for production of unnatural amino acids.
Background
Chiral amino acids and derivatives are important intermediates in chemical, pharmaceutical and biological synthesis, and play an important role in protein and polypeptide research. The simplest and convenient methods for synthesizing chiral amino acid esters include asymmetric hydrogenation of dehydroamino acid esters and asymmetric hydrogenation of alpha-imino acid esters. Wherein, the asymmetric hydrogenation of the alpha-imine acid ester is a green, environment-friendly and efficient method for synthesizing the chiral aromatic amino acid ester. The chiral aromatic amino acid ester compound is prepared by directly hydrogenating an alpha-imino ester substrate with the help of a chiral catalyst and other auxiliary agents. In recent years, there has been great progress on organic small molecule catalyzed asymmetric transfer hydrogenation of α -imidates, while there have been few reports on metal catalyzed asymmetric hydrogenation of α -imidates.
In 2001, the Amii team (H.Abe, H.Amii, K.Unneyama.org.Lett.2001, 3,313-315; the) successfully catalyzed asymmetric hydrogenation of alpha-imidate to chiral amino acid ester derivatives using (R) - (+) -1,1 '-binaphthyl-2,2' -bis-diphenylphosphine ligand and palladium trifluoroacetate, achieved up to 91% enantioselectivity. However, this method is suitable only for small amounts of substrate.
In 2006, the Zhang Xumu team (g.shang, q.yang, x.zhang.angelw.chem.2006, 118,6508-6510; angelw.chem.int.ed.2006, 45, 6360-6362) reported asymmetric hydrogenation of aromatic alpha-imidate, and a chiral alpha-aryl amino acid ester product could be obtained under catalysis of Rh- (S, R) -tandphos, with a product yield of more than 93% and an enantioselectivity up to 95%.
Therefore, the development of the catalyst which has high activity and stereoselectivity and is suitable for the widely asymmetric reduction of the alpha-imine acid ester on the substrate has very important significance.
Disclosure of Invention
The invention aims to provide a method for synthesizing chiral alpha-amino acid ester derivatives.
In order to achieve the purpose, the technical scheme of the invention is as follows:
a method for synthesizing chiral alpha-amino acid ester derivatives, which adopts chiral catalysts iridium-L and alpha-imino acid ester to prepare chiral amino acid ester derivatives by asymmetric hydrogenation; the chiral catalyst iridium-L is generated by in-situ coordination of an iridium-cyclooctadiene complex and a chiral ferrocene skeleton phosphine-phosphoramidite ligand in a solvent.
A method for synthesizing chiral alpha-amino acid ester derivatives comprises the following steps:
under the protection of nitrogen, dissolving an iridium-cyclooctadiene complex and a chiral ferrocene skeleton phosphine-phosphoramidite ligand in a solvent, stirring for 10 minutes at room temperature, adding a substrate alpha-imino ester and an additive (10 mol%) dissolved in the solvent, placing the mixture into a high-pressure reaction kettle, performing hydrogen replacement for 3 times, introducing hydrogen to 20-100bar, reacting for 1-24 hours at-20-50 ℃, slowly releasing the hydrogen, removing the solvent, and separating by using a silica gel column (eluent: ethyl acetate/petroleum ether = 1/10) to obtain the chiral alpha-amino acid ester derivative.
The solvent is tetrahydrofuran, dioxane, dichloromethane, 1,2-dichloroethane or toluene; tetrahydrofuran and dioxane are preferred.
The additive is iodine, N-iodosuccinimide, N-bromosuccinimide, N-chlorosuccinimide or tetrabutylammonium iodide; iodine, N-iodosuccinimide, are preferred.
In order to achieve the purpose, the technical scheme of the invention is as follows:
the imidate and the prepared chiral amino acid ester related by the invention have the following structures:
in the formula:
R 1 is C 1 ～C 10 Alkyl radicals such as CH 3 、CH 3 CH 2 Etc. C 3 ～C 12 Cycloalkyl radicals such as cyclopentyl, cyclohexyl, etc., or C containing one or more functional groups of N, S, O, P 1 ～C 10 Alkyl such as methoxymethyl, ethoxymethyl, etc., or C containing one or more than two functional groups of N, S, O, P 3 ～C 10 Cycloalkyl groups such as 2-tetrahydrofuryl, 4-tetrahydrofuryl, etc.; or aryl or the like C 6 -C 30 Aromatic groups with or without N, S, O, P or the like functional groups, e.g., phenyl, 4-methoxyphenyl, or the like
R 2 Is aryl or the like C 6 -C 30 Aromatic groups such as phenyl, 4-methoxyphenyl, etc., with or without N, S, O, P, etc., functional groups;
R 3 is C 1 ～C 10 Alkyl radicals such as CH 3 、CH 3 CH 2 And the like.
The chiral ferrocene skeleton phosphine-phosphoramidite ligand has the following structure:
in the formula, R 1 、R 2 Is H; alkyl and cycloalkyl radicals and the like C 1 ～C 40 Aliphatic groups containing or not containing N, S, O, P and other functional groups; benzyl radical or the like C 7 -C 60 A combination group of aromatic group and aliphatic group containing or not containing N, S, O, P and other functional groups; aryl and the like C 6 -C 60 Aromatic groups with or without N, S, O, P and the like.
Ar is C 6 -C 60 Aromatic groups with or without N, S, O, P and the like.
The X group is: chiral or achiral aliphatic groups with or without functional groups such as N, S, O, P; aromatic groups with or without N, S, O, P functional groups; chiral or achiral biphenyl, binaphthyl or tetrahydrobinaphthyl aromatic groups containing or not containing N, S, O, P and other functional groups.
The iridium-cyclooctadiene complex is: [ Ir (COD) Cl] 2 、Ir(COD) 2 BF 4 Or Ir (COD) 2 BARF。
The iridium concentration in the reaction system is 0.001-0.01mol/l, and the molar ratio of the chiral ferrocene skeleton phosphine-phosphoramidite ligand to iridium is 1-5:1; preferably, the iridium concentration is 0.002mol/l and the molar ratio of ligand to iridium is 1:1.
The molar ratio of the alpha-imidate substrate to the chiral catalyst iridium-L is 50-500:1; preferably 50 to 100.
The invention has the beneficial effects that: compared with other methods for synthesizing chiral amino acid ester, the method for synthesizing the hydrogenated chiral ferrocene skeleton phosphine-phosphoramidite ligand is simple, low in price and suitable for kilogram-level production, the iridium/chiral ferrocene skeleton phosphine-phosphoramidite system is high in catalytic activity and enantioselectivity, the enantiomeric excess (ee value) of the product is up to more than 96%, the hydrogenation reaction is simple to operate, mild in condition and high in atom economy, and the method is suitable for industrial production, has a good result on the synthesis of phenylglycine ethyl ester, achieves the yield of 92% and the enantioselectivity of 91%, and has good industrial practicability.
Drawings
In order to more clearly illustrate the technical solutions of the embodiments of the present invention, the drawings needed to be used in the embodiments will be briefly described below, it should be understood that the following drawings only illustrate some embodiments of the present invention and therefore should not be considered as limiting the scope, and for those skilled in the art, other related drawings can be obtained according to the drawings without inventive efforts.
FIG. 1: nuclear magnetic resonance hydrogen spectrum of methyl (4-methoxyanilino) phenylacetate prepared in example 1;
FIG. 2: nuclear magnetic resonance carbon spectrum of methyl (4-methoxyanilino) phenylacetate prepared in example 1;
FIG. 3: NMR spectrum of methyl (4-methylphenyl) - (4-methoxyanilino) acetate prepared in example 15;
FIG. 4: nuclear magnetic resonance carbon spectrum of methyl (4-methylphenyl) - (4-methoxyanilino) acetate prepared in example 15;
FIG. 5: nuclear magnetic resonance hydrogen spectrum of methyl (4-methoxyphenyl) - (4-methoxyanilino) acetate prepared in example 16;
FIG. 6: nuclear magnetic resonance carbon spectrum of methyl (4-methoxyphenyl) - (4-methoxyanilino) acetate prepared in example 16;
FIG. 7: nuclear magnetic resonance hydrogen spectrum of methyl (3-methoxyphenyl) - (4-methoxyanilino) acetate prepared in example 17;
FIG. 8: nuclear magnetic resonance carbon spectrum of methyl (3-methoxyphenyl) - (4-methoxyanilino) acetate prepared in example 17;
FIG. 9: nuclear magnetic resonance hydrogen spectrum of methyl (2-methoxyphenyl) - (4-methoxyanilino) acetate prepared in example 18;
FIG. 10: nuclear magnetic resonance carbon spectrum of methyl (2-methoxyphenyl) - (4-methoxyanilino) acetate prepared in example 18;
FIG. 11: nuclear magnetic resonance hydrogen spectrum of methyl (4-fluorophenyl) - (4-methoxyanilino) acetate prepared in example 19;
FIG. 12: nuclear magnetic resonance carbon spectrum of methyl (4-fluorophenyl) - (4-methoxyanilino) acetate prepared in example 19;
FIG. 13: NMR spectrum of methyl (4-chlorophenyl) - (4-methoxyanilino) acetate prepared in example 20;
FIG. 14 is a schematic view of: NMR carbon spectrum of methyl (4-chlorophenyl) - (4-methoxyanilino) acetate prepared in example 20;
FIG. 15: NMR spectrum of methyl (3-chlorophenyl) - (4-methoxyanilino) acetate prepared in example 21;
FIG. 16: nuclear magnetic resonance carbon spectrum of methyl (3-chlorophenyl) - (4-methoxyanilino) acetate prepared in example 21;
FIG. 17: NMR spectrum of methyl (4-bromophenyl) - (4-methoxyanilino) acetate prepared in example 22;
FIG. 18: nuclear magnetic resonance carbon spectrum of methyl (4-bromophenyl) - (4-methoxyanilino) acetate prepared in example 22;
FIG. 19: nuclear magnetic resonance hydrogen spectrum of methyl (4-trifluoromethylphenyl) - (4-methoxyanilino) acetate prepared in example 23;
FIG. 20: nuclear magnetic resonance carbon spectrum of methyl (4-trifluoromethylphenyl) - (4-methoxyanilino) acetate prepared in example 23;
FIG. 21: nuclear magnetic resonance hydrogen spectrum of methyl (2-naphthyl) - (4-methoxyanilino) acetate prepared in example 24;
FIG. 22: nuclear magnetic resonance carbon spectrum of methyl (2-naphthyl) - (4-methoxyanilino) acetate prepared in example 24;
FIG. 23: nuclear magnetic resonance hydrogen spectrum of methyl (2-thienyl) - (4-methoxyanilino) acetate prepared in example 25;
FIG. 24: nuclear magnetic resonance carbon spectrum of methyl (2-thienyl) - (4-methoxyanilino) acetate prepared in example 25;
FIG. 25 is a schematic view of: nuclear magnetic resonance hydrogen spectrum of methyl (cyclohexyl) - (4-methoxyanilino) acetate prepared in example 26;
FIG. 26: nuclear magnetic resonance carbon spectrum of methyl (cyclohexyl) - (4-methoxyanilino) acetate prepared in example 26;
FIG. 27 is a schematic view showing: nuclear magnetic resonance hydrogen spectrum of ethyl phenyl (4-methoxyanilino) acetate prepared in example 27;
FIG. 28: nuclear magnetic resonance carbon spectrum of ethyl phenyl (4-methoxyanilino) acetate prepared in example 27;
FIG. 29: nuclear magnetic resonance hydrogen spectrum of isopropyl phenyl (4-methoxyanilino) acetate prepared in example 28;
FIG. 30: nuclear magnetic resonance carbon spectrum of isopropyl phenyl (4-methoxyanilino) acetate prepared in example 28;
FIG. 31: nuclear magnetic resonance hydrogen spectrum of methyl phenyl (4-methoxyanilino) acetate prepared in example 29;
FIG. 32: NMR carbon spectrum of methyl phenyl (4-methoxyanilino) acetate prepared in example 29.
Detailed Description
The following examples further illustrate the invention but are not intended to limit the invention thereto. NMR was measured by Bruker NMR and High Performance Liquid Chromatography (HPLC) was measured by Agilent 1100 series HPLC.
Example 1
Under the protection of nitrogen gas, [ Ir (COD) Cl] 2 (0.002mmol, 0.5 mol%), chiral ferrocene skeleton phosphine-phosphoramidite ligand (0.0048mmol, 1.1mol%) was dissolved in tetrahydrofuran (1.0 mL), stirred at room temperature for 10 minutes, a solution of methyl phenylacetate (0.4 mmol) as a substrate (4-methoxyphenylimino) in tetrahydrofuran (1.0 mL) and 5.1mg of iodine were added, and the mixture was placed in a high-pressure reaction vessel, replaced with hydrogen gas for 3 times, and then charged with hydrogen gas to 50 atmospheres, and reacted at 25 ℃ for 24 hours. Slowly releasing hydrogen, removing the solvent, and separating by using a silica gel column to obtain the product.
The product was analyzed by detection and the NMR and HPLC data are as follows:
Yellow oil was obtained in 96％yield after purification with column chromatography on silica gel (hexanes/ethyl acetate,10/1).92％ee was determined by chiral HPLC(Chiralcel OJ-H, n-hexane/i-PrOH＝70/30,0.8ml/min,254nm,40℃):t R (minor)＝26.8min,t R (major)＝29.0min. [α] 25 D ＝100(c 0.88,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.52–7.44(m,2H),7.39–7.26(m, 3H),6.79–6.65(m,2H),6.60–6.45(m,2H),5.01(s,1H),4.67(s,1H),3.71(s,3H),3.69(s,3H). 13 C NMR(101MHz,CDCl 3 )δ172.58(s),152.54(s),140.21(s),137.81(s),128.88(s),128.30(s), 127.30(s),114.83(d,J＝8.3Hz),77.39(s),77.07(s),76.76(s),61.67(s),55.70(s),52.74(s).
the detection result shows that the product is as follows: (4-Methoxyanilino) phenylacetic acid methyl ester.
Example 2
The reaction conditions H in example 1 were 2 The pressure was changed to 100 atmospheres, and the reaction was carried out as in example 1 to give a product which was, upon detection, methyl (4-methoxyanilino) phenylacetate in 98% yield and enantioselectivity 92% ee.
Example 3
The reaction conditions H in example 1 were 2 The pressure was changed to 20 atmospheres, and the reaction was carried out as in example 1 to give a product which was found to be (4-methoxyanilino) methyl phenylacetate in a yield of 76% and an enantioselectivity of 90% ee.
Example 4
The reaction was carried out in the same manner as in example 1 except that the temperature was changed to 25 ℃ in the reaction conditions of example 1 to obtain a product, which was detected to be methyl (4-methoxyanilino) phenylacetate, yield 93%, enantioselectivity 91% by volume ee.
Example 5
The reaction was carried out in the same manner as in example 1 except that the temperature of the reaction conditions in example 1 was changed to 50 ℃ to obtain a product, which was detected to be methyl (4-methoxyanilino) phenylacetate, yield 95%, enantioselectivity 80% ee.
Example 6
The reaction conditions in example 4 were changed to N-iodosuccinimide, and the remainder of the reaction was carried out in the same manner as in example 4 to give a product which was detected to be (4-methoxyanilino) methyl phenylacetate in 95% yield and enantioselectivity 83% ee.
Example 7
The reaction conditions in example 4 were changed to N-bromosuccinimide, and the remainder of the reaction was carried out in the same manner as in example 4 to give a product which was detected to be (4-methoxyanilino) methyl phenylacetate in 53% yield and enantioselectivity 67% ee.
Example 8
The reaction was carried out in the same manner as in example 6 except that the solvent used in the reaction conditions in example 6 was changed to methylene chloride to give a product, which was detected to be methyl (4-methoxyanilino) phenylacetate, yield 93%, enantioselectivity 69% ee.
Example 9
The reaction was carried out in the same manner as in example 6 except that the solvent used in the reaction conditions in example 6 was changed to dichloroethane, and the reaction product was found to be methyl (4-methoxyanilino) phenylacetate in a yield of 93% and an enantioselectivity of 67% ee.
Example 10
The reaction was carried out in the same manner as in example 6 except that the solvent used in the reaction conditions in example 6 was changed to toluene to obtain a product, which was found to be methyl (4-methoxyanilino) phenylacetate in a yield of 94% and an enantioselectivity of 77% ee.
Example 11
The reaction conditions in example 6 were changed to 3,3' -dihydro-substituted ferrocenylphosphine-phosphoramidite and the remainder of the reaction was carried out as in example 6 to give the product which was found to be (4-methoxyanilino) methyl phenylacetate in 94% yield and 63% enantioselectivity ee.
Example 12
The reaction conditions in example 6 were changed to 3,3' -methyl substituted ferrocenylphosphine-phosphoramidite and the remainder of the reaction was performed as in example 6 to give the product which was detected to be (4-methoxyanilino) methyl phenylacetate in 95% yield and 74% enantioselectivity in 74% ee.
Example 13
The reaction conditions in example 6 were changed to 3,3' -phenyl substituted ferrocenylphosphine-phosphoramidite and the remainder of the reaction was the same as in example 6 to give the product which was detected to be (4-methoxyanilino) phenylacetic acid methyl ester in 43% yield and enantioselectivity 51% ee.
Example 14
The substrate to catalyst ratio in example 1 was changed to S/C =1000, i.e.: [ Ir (COD) Cl] 2 (0.00025mmol, 0.05 mol%) chiral phosphine-phosphoramidite ligand (0.00055mmol, 0.11mol%) was reacted to give the product, which was detected as methyl (4-methoxyanilino) phenylacetate, with an enantioselectivity of 80% ee.
Example 15
The substrate in example 1 was changed to methyl (4-methylphenyl) - (4-methoxyphenylimino) acetate, and the reaction was carried out in the same manner as in example 1 to obtain a product.
The product was analyzed and the NMR and HPLC data are as follows:
Yellow oil was obtained in 96％yield after purification with column chromatography on silica gel (hexanes/ethyl acetate,10/1).93％ee was determined by chiral HPLC(Chiralcel OJ-H, n-hexane/i-PrOH＝90/10,0.8ml/min,254nm,40℃):t R (major)＝33.8min,t R (minor)＝37.2min. [α] 25 D ＝100(c 1.02,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.36(d,J＝8.0Hz,2H),7.15(d,J＝ 8.0Hz,2H),6.75–6.66(m,2H),6.58–6.46(m,2H),4.98(s,1H),4.62(s,1H),3.70(s,3H),3.69 (s,3H),2.32(s,3H). 13 C NMR(101MHz,CDCl 3 )δ172.75(s),152.49(s),140.29(s),138.08(s), 134.80(s),129.58(s),127.19(s),114.82(d,J＝9.7Hz),77.39(s),77.08(s),76.76(s),61.38(s), 55.70(s),52.69(s),21.16(s).
the detection result shows that the product is as follows: (4-methylphenyl) - (4-methoxyanilino) acetic acid methyl ester.
Example 16
The substrate in example 1 was changed to methyl (4-methoxyphenyl) - (4-methoxyphenylimino) acetate, and the reaction was carried out in the same manner as in example 1 to obtain a product.
The product was analyzed and the NMR and HPLC data are as follows:
Yellow solid was obtained in 97％yield after purification with column chromatography on silica gel(hexanes/ethyl acetate,10/1).95％ee was determined by chiral HPLC(Chiralcel OJ-H, n-hexane/i-PrOH＝70/30,0.8ml/min,254nm,40℃):t R (minor)＝31.9min,t R (major)＝36.8min. [α] 25 D ＝82.4(c 0.93,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.39(d,J＝8.7Hz,2H),6.87(d,J＝ 8.7Hz,2H),6.72(d,J＝8.9Hz,2H),6.53(d,J＝8.9Hz,2H),4.96(s,1H),4.61(s,1H),3.78(s, 3H),3.71(s,3H),3.70(s,3H). 13 C NMR(101MHz,CDCl 3 )δ172.83(s),159.56(s),152.50(s), 140.26(s),129.74(s),128.43(s),114.82(d,J＝7.7Hz),114.26(s),77.37(s),77.05(s),76.74(s), 61.02(s),55.70(s),55.28(s),52.67(s),29.72(s).
the detection result shows that the product is as follows: (4-methoxyphenyl) - (4-methoxyanilino) acetic acid methyl ester.
Example 17
The substrate in example 1 was changed to methyl (3-methoxyphenyl) - (4-methoxyphenylimino) acetate, and the reaction was carried out in the same manner as in example 1 to obtain a product.
The product was analyzed and the NMR and HPLC data are as follows:
Yellow oil was obtained in 95％yield after purification with column chromatography on silica gel (hexanes/ethyl acetate,10/1).87％ee was determined by chiral HPLC(Chiralpak OJ-H, n-hexane/i-PrOH＝70/30,0.8ml/min,254nm,40℃):t R (minor)＝29.7min,t R (major)＝34.0min. [α] 25 D ＝83.7(c 1.05,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.26(dd,J＝9.9,5.9Hz,1H),7.05 (dd,J＝14.5,4.9Hz,2H),6.84(dd,J＝8.2,2.4Hz,1H),6.76–6.66(m,2H),6.57–6.47(m,2H), 4.98(s,1H),4.65(s,1H),3.79(s,3H),3.72(s,3H),3.70(s,3H). 13 C NMR(101MHz,CDCl 3 )δ 172.47(s),160.00(s),152.54(s),140.21(s),139.42(s),129.86(s),119.64(s),114.82(d,J＝8.7 Hz),113.74(s),112.84(s),77.36(s),77.04(s),76.73(s),61.66(s),55.70(s),55.27(s),52.77(s).
the detection result shows that the product is as follows: (3-methoxyphenyl) - (4-methoxyanilino) acetic acid methyl ester.
Example 18
The substrate in example 1 was changed to methyl (2-methoxyphenyl) - (4-methoxyphenylimino) acetate, and the reaction was carried out in the same manner as in example 1 to obtain a product.
The product was analyzed and the NMR and HPLC data are as follows:
Yellow oil was obtained in 93％yield after purification with column chromatography on silica gel (hexanes/ethyl acetate,10/1).77％ee was determined by chiral HPLC(Chiralpak OJ-H, n-hexane/i-PrOH＝70/30,0.8ml/min,254nm,40℃):t R (minor)＝30.2min,t R (major)＝35.9min. [α] 25 D ＝82.1(c 1.0,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.34(dd,J＝7.4,1.3Hz,1H),7.30–7.21(m,1H),6.92(t,J＝7.9Hz,2H),6.75–6.66(m,2H),6.67–6.53(m,2H),5.44(s,1H),4.59 (s,1H),3.89(s,3H),3.69(s,3H),3.68(s,3H). 13 C NMR(101MHz,CDCl 3 )δ173.09(s),157.14 (s),152.58(s),140.65(s),129.43(s),128.18(s),126.53(s),121.05(s),115.09(s),114.79(s), 111.20(s),77.41(s),77.10(s),76.78(s),55.97–55.58(m),52.54(s).
the detection result shows that the product is: (2-methoxyphenyl) - (4-methoxyanilino) acetic acid methyl ester.
Example 19
The substrate in example 1 was changed to methyl (4-fluorophenyl) - (4-methoxyphenylimino) acetate, and the reaction was carried out in the same manner as in example 1 to obtain a product.
The product was analyzed by detection and the NMR and HPLC data are as follows:
Yellow oil was obtained in 92％yield after purification with column chromatography on silica gel (hexanes/ethyl acetate,10/1).93％ee was determined by chiral HPLC(Chiralpak AD-H, n-hexane/i-PrOH＝80/20,0.8ml/min,254nm,40℃):t R (major)＝11.2min,t R (minor)＝12.6min. [α] 25 D ＝88.0(c 0.74,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.51–7.41(m,2H),7.09–6.97(m, 2H),6.77–6.66(m,2H),6.55–6.44(m,2H),4.99(s,1H),4.68(s,1H),3.72(s,3H),3.70(s,3H). 13 C NMR(101MHz,CDCl 3 )δ172.33(s),163.86(s),161.40(s),152.62(s),139.94(s),133.57(d, J＝3.1Hz),128.94(d,J＝8.2Hz),115.90(s),115.68(s),114.84(d,J＝8.2Hz),99.99(s),77.36 (s),77.05(s),76.73(s),60.93(s),55.69(s),52.83(s).
the detection result shows that the product is as follows: (4-fluorophenyl) - (4-methoxyanilino) acetic acid methyl ester.
Example 20
The substrate in example 1 was changed to methyl (4-chlorophenyl) - (4-methoxyphenylimino) acetate, and the reaction was carried out in the same manner as in example 1 to obtain a product.
The product was analyzed by detection and the NMR and HPLC data are as follows:
Yellow oil was obtained in 98％yield after purification with column chromatography on silica gel (hexanes/ethyl acetate,10/1).93％ee was determined by chiral HPLC(Chiralpak OJ-H, n-hexane/i-PrOH＝90/10,0.8ml/min,254nm,40℃):t R (major)＝32.2min,t R (minor)＝35.7min. [α] 25 D ＝112.7(c 0.93,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.43(d,J＝8.5Hz,2H),7.37–7.28 (m,2H),6.81–6.64(m,2H),6.59–6.37(m,2H),4.98(s,1H),4.70(s,1H),3.72(s,3H),3.70(s, 3H). 13 C NMR(101MHz,CDCl 3 )δ172.05(s),152.65(s),139.82(s),136.42(s),134.11(s), 129.04(s),128.65(s),114.84(d,J＝9.4Hz),77.37(s),77.05(s),76.73(s),60.99(s),55.69(s), 52.90(s).
the detection result shows that the product is: (4-chlorophenyl) - (4-methoxyanilino) acetic acid methyl ester.
Example 21
The substrate in example 1 was changed to methyl (3-chlorophenyl) - (4-methoxyphenylimino) acetate, and the reaction was carried out in the same manner as in example 1 to obtain a product.
The product was analyzed and the NMR and HPLC data are as follows:
Yellow oil was obtained in 95％yield after purification with column chromatography on silica gel (hexanes/ethyl acetate,10/1).86％ee was determined by chiral HPLC(Chiralpak OJ-H, n-hexane/i-PrOH＝90/10,0.8ml/min,254nm,40℃):t R (minor)＝36.1min,t R (major)＝38.3min. [α] 25 D ＝85.0(c 0.84,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.50(s,1H),7.38(td,J＝4.6,1.6Hz, 1H),7.32–7.22(m,2H),6.78–6.64(m,2H),6.59–6.39(m,2H),4.97(s,1H),4.72(s,1H),3.73 (s,3H),3.70(s,3H). 13 C NMR(101MHz,CDCl 3 )δ171.88(s),152.68(s),140.05(s),139.81(s), 134.78(s),130.10(s),128.52(s),127.46(s),125.47(s),114.85(d,J＝12.2Hz),77.37(s),77.05 (s),76.73(s),61.19(s),55.70(s),52.96(s).
the detection result shows that the product is as follows: (3-chlorophenyl) - (4-methoxyanilino) acetic acid methyl ester.
Example 22
The substrate in example 1 was changed to methyl (4-bromophenyl) - (4-methoxyphenylimino) acetate, and the reaction was carried out in the same manner as in example 1 to obtain a product.
The product was analyzed by detection and the NMR and HPLC data are as follows:
Yellow oil was obtained in 97％yield after purification with column chromatography on silica gel (hexanes/ethyl acetate,10/1).93％ee was determined by chiral HPLC(Chiralpak OJ-H, n-hexane/i-PrOH＝90/10,0.8ml/min,254nm,40℃):t R (major)＝33.6min,t R (minor)＝37.6min. [α] 25 D ＝94.1(c 1.06,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.52–7.42(m,2H),7.37(d,J＝8.5 Hz,2H),6.78–6.64(m,2H),6.56–6.41(m,2H),4.97(s,1H),4.71(s,1H),3.72(s,3H),3.70(s, 3H). 13 C NMR(101MHz,CDCl 3 )δ171.96(s),152.65(s),139.79(s),136.97(s),131.99(s), 129.00(s),122.26(s),114.85(d,J＝9.7Hz),77.38(s),77.07(s),76.75(s),61.05(s),55.69(s), 52.92(s).
the detection result shows that the product is as follows: (4-bromophenyl) - (4-methoxyanilino) acetic acid methyl ester.
Example 23
The substrate in example 1 was changed to methyl (4-trifluoromethylphenyl) - (4-methoxyphenylimino) acetate, and the remainder was changed to
Example 1, the reaction yielded the product.
The product was analyzed and the NMR and HPLC data are as follows:
Yellow oil was obtained in 97％yield after purification with column chromatography on silica gel (hexanes/ethyl acetate,10/1).92％ee was determined by chiral HPLC(Chiralpak AS-H, n-hexane/i-PrOH＝95/5,0.8ml/min,254nm,40℃):t R (minor)＝11.3min,t R (major)＝15.3min. [α] 25 D ＝74.5(c 0.86,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.77–7.50(m,4H),6.80–6.63(m, 2H),6.58–6.36(m,2H),5.07(s,1H),4.78(s,1H),3.74(s,3H),3.70(s,3H). 13 C NMR(101MHz, CDCl 3 )δ171.66(s),152.73(s),142.01(s),139.65(s),130.66(s),127.69(s),125.82(d,J＝3.7Hz), 114.85(d,J＝14.5Hz),77.35(s),77.03(s),76.71(s),61.27(s),55.67(s),53.03(s).
the detection result shows that the product is as follows: (4-trifluoromethylphenyl) - (4-methoxyanilino) acetic acid methyl ester.
Example 24
The substrate in example 1 was changed to methyl (2-naphthyl) - (4-methoxyphenylimino) acetate, and the reaction was carried out in the same manner as in example 1 to obtain a product.
The product was analyzed and the NMR and HPLC data are as follows:
Yellow oil was obtained in 94％yield after purification with column chromatography on silica gel (hexanes/ethyl acetate,10/1).80％ee was determined by chiral HPLC(Chiralpak AS-H, n-hexane/i-PrOH＝95/5,0.8ml/min,254nm,40℃):t R (major)＝24.1min,t R (minor)＝37.5min. [α] 25 D ＝84.0(c 0.97,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.95(s,1H),7.87–7.76(m,3H), 7.59(dd,J＝8.5,1.6Hz,1H),7.53–7.38(m,2H),6.75–6.63(m,2H),6.65–6.49(m,2H),5.17 (s,1H),4.81(s,1H),3.70(s,3H),3.67(s,3H). 13 C NMR(101MHz,CDCl 3 )δ172.54(s),152.58 (s),140.22(s),135.36(s),133.35(d,J＝11.1Hz),128.77(s),128.09(s),127.74(s),126.62– 126.19(m),125.00(s),114.89(d,J＝3.7Hz),77.41(s),77.09(s),76.78(s),61.85(s),55.70(s), 52.82(s).
the detection result shows that the product is as follows: (2-naphthyl) - (4-methoxyanilino) acetic acid methyl ester.
Example 25
The substrate in example 1 was changed to methyl (2-thienyl) - (4-methoxyphenylimino) acetate, and the reaction was carried out in the same manner as in example 1 to obtain a product.
The product was analyzed by detection and the NMR and HPLC data are as follows:
Yellow oil was obtained in 90％yield after purification with column chromatography on silica gel (hexanes/ethyl acetate,10/1).53％ee was determined by chiral HPLC(Chiralpak AS-H, n-hexane/i-PrOH＝95/5,0.8ml/min,254nm,40℃):t R (major)＝17.7min,t R (minor)＝21.5min. [α] 25 D ＝31.8(c 1.02,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.26–7.20(m,1H),7.12(d,J＝3.5 Hz,1H),6.97(dd,J＝5.0,3.6Hz,1H),6.78–6.70(m,2H),6.65–6.54(m,2H),5.28(s,1H),4.64 (s,1H),3.77(s,3H),3.71(s,3H). 13 C NMR(101MHz,CDCl 3 )δ171.69(s),153.01(s),141.49(s), 139.95(s),127.10(s),125.58(d,J＝11.2Hz),115.27(s),114.87(s),77.40(s),77.08(s),76.76(s), 57.83(s),55.67(s),52.95(s).
the detection result shows that the product is as follows: (2-thienyl) - (4-methoxyanilino) acetic acid methyl ester.
Example 26
The substrate in example 1 was changed to methyl (cyclohexyl) - (4-methoxyphenylimino) acetate, and the reaction was carried out in the same manner as in example 1 to obtain a product.
The product was analyzed by detection and the NMR and HPLC data are as follows:
Yellow oil was obtained in 91％yield after purification with column chromatography on silica gel (hexanes/ethyl acetate,10/1).73％ee was determined by chiral HPLC(Chiralpak AS-H, n-hexane/i-PrOH＝95/5,0.8ml/min,254nm,40℃):t R (minor)＝7.0min,t R (major)＝7.9min. [α] 25 D ＝-45.2(c 0.88,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ6.81–6.70(m,2H),6.66–6.51(m, 2H),3.86(d,J＝2.5Hz,1H),3.78(d,J＝6.2Hz,1H),3.73(s,3H),3.68(s,3H),1.86(d,J＝12.5 Hz,1H),1.82–1.59(m,6H),1.34–1.07(m,5H). 13 C NMR(101MHz,CDCl 3 )δ174.59(s), 152.66(s),141.58(s),115.14(s),114.89(s),77.37(s),77.05(s),76.73(s),63.39(s),55.73(s), 51.75(s),41.33(s),29.72(s),29.25(s),26.14(d,J＝10.9Hz).
the detection result shows that the product is as follows: (cyclohexyl) - (4-methoxyanilino) acetic acid methyl ester.
Example 27
The substrate in the example 1 is changed into phenyl (4-methoxy phenylimino) ethyl acetate, and the reaction is carried out in the same way as the example 1 to obtain the product.
The product was analyzed and the NMR and HPLC data are as follows:
Yellow oil was obtained in 94％yield after purification with column chromatography on silica gel (hexanes/ethyl acetate,10/1).93％ee was determined by chiral HPLC(Chiralpak AS-H, n-hexane/i-PrOH＝95/5,0.8ml/min,254nm,40℃):t R (major)＝11.0min,t R (minor)＝12.3min. [α] 25 D ＝71.7(c 0.96,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.48(d,J＝7.2Hz,2H),7.41–7.19 (m,3H),6.79–6.64(m,2H),6.63–6.38(m,2H),5.00(s,1H),4.76–4.44(m,1H),4.33–4.04(m, 2H),3.69(s,3H),1.20(t,J＝7.1Hz,3H). 13 C NMR(101MHz,CDCl 3 )δ172.06(s),152.48(s), 140.27(s),137.92(s),128.80(s),128.19(s),127.25(s),114.81(d,J＝8.7Hz),77.38(s),77.06(s), 76.74(s),61.72(s),55.70(s),14.06(s).
the detection result shows that the product is as follows: phenyl (4-methoxyanilino) acetic acid ethyl ester.
Example 28
The substrate in the example 1 is changed into phenyl (4-methoxy phenylimino) isopropyl acetate, and the reaction is carried out in the same way as the example 1 to obtain the product.
The product was analyzed and the NMR and HPLC data are as follows:
Yellow oil was obtained in 96％yield after purification with column chromatography on silica gel (hexanes/ethyl acetate,10/1).96％ee was determined by chiral HPLC(Chiralpak AS-H, n-hexane/i-PrOH＝95/5,0.8ml/min,254nm,40℃):t R (major)＝8.5min,t R (minor)＝9.5min. [α] 25 D ＝65.9(c 0.94,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.40(d,J＝7.3Hz,2H),7.22(ddd,J ＝15.7,13.9,6.5Hz,3H),6.64(dd,J＝9.6,2.7Hz,2H),6.46(t,J＝6.2Hz,2H),4.94(dt,J＝12.5, 6.3Hz,1H),4.89(s,1H),4.59(s,1H),3.62(s,3H),1.18(d,J＝6.3Hz,3H),0.99(d,J＝6.2Hz, 3H). 13 C NMR(101MHz,CDCl 3 )δ171.57(s),152.43(s),140.34(s),137.97(s),128.72(s), 128.09(s),127.17(s),114.80(d,J＝9.7Hz),77.38(s),77.06(s),76.74(s),69.35(s),61.80(s), 55.71(s),21.78(s),21.39(s).
the detection result shows that the product is as follows: isopropyl phenyl (4-methoxyanilino) acetate.
Example 29
The substrate in example 1 was changed to methyl phenyl (4-phenylimino) acetate, and the reaction was carried out in the same manner as in example 1 to obtain a product.
The product was analyzed by detection and the NMR and HPLC data are as follows:
Yellow oil was obtained in 95％yield after purification with column chromatography on silica gel (hexanes/ethyl acetate,10/1).90％ee was determined by chiral HPLC(Chiralcel OD-H, n-hexane/i-PrOH＝99/1,0.8ml/min,254nm,40℃):t R (major)＝32.9min,t R (minor)＝41.2min. [α] D 23 ＝93.7(c 0.94,CH 2 Cl 2 ). 1 H NMR(400MHz,CDCl 3 )δ7.52–7.45(m,2H),7.39–7.26(m, 3H),7.11(t,J＝7.9Hz,2H),6.69(t,J＝7.3Hz,1H),6.55(d,J＝7.9Hz,2H),5.08(d,J＝5.8Hz, 1H),4.95(d,J＝5.5Hz,1H),3.72(s,3H). 13 C NMR(101MHz,CDCl 3 )δ172.36(s),145.96(s), 137.63(s),129.26(s),128.91(s),128.34(s),127.27(s),118.14(s),113.42(s),77.38(s),77.06(s), 76.74(s),60.76(s),52.83(s).
the detection result shows that the product is as follows: phenyl (4-methoxyanilino) acetic acid methyl ester.
Table.Asymmetric hydrogenation ofα-imino esters a)
a) Conditions:5(0.2mmol),[Ir(COD)Cl] 2 (2μmol),ligand 2d(4.8μmol),H 2 (50bar),THF (2.0ml),I 2 (10mol％),24h,0℃. b) Isolated yields. c) Determined by chiral HPLC。
Claims (4)
1. A method for synthesizing chiral alpha-amino acid ester derivatives is characterized in that: the method takes an alpha-imidic acid ester compound as a raw material and an iridium/chiral ferrocene skeleton phosphine-phosphoramidite ligand as a catalyst to prepare the chiral alpha-amino acid ester derivative, and the reaction equation is as follows:
in the formula:
R 1 is C 1 ～C 10 Alkyl radical, C 3 ～C 12 Cycloalkyl, or C containing one or more than two functional groups of N, S, O, P 1 ～C 10 Alkyl, or C containing one or more than two functional groups of N, S, O, P 3 ～C 10 A cycloalkyl group; or C 6 -C 30 An aromatic group with or without N, S, O, P functionality;
R 2 is C 6 -C 30 Aromatic groups with or without N, S, O, P functionality;
R 3 is C 1 ～C 10 An alkyl group;
the general formula of the chiral ferrocene skeleton phosphine-phosphoramidite ligand L is as follows:
(ii) a Wherein R is 1 、R 2 Is methyl, ar is phenyl, X is a chiral binaphthyl aromatic group;
the method specifically comprises the following steps:
under the protection of nitrogen, dissolving an iridium-cyclooctadiene complex and a chiral ferrocene skeleton phosphine-phosphoramidite ligand in a solvent, stirring for 10 minutes at room temperature, adding a substrate alpha-imino acid ester and an additive which are dissolved in the solvent, placing the mixture in a high-pressure reaction kettle, performing hydrogen displacement for 3 times, then introducing hydrogen to 20-100bar, reacting for 1-24 hours at-20-50 ℃, slowly releasing the hydrogen, removing the solvent, separating by using a silica gel column, and eluting by using an eluent with ethyl acetate/petroleum ether =1/10 to obtain a product chiral alpha-amino acid ester derivative;
the mole percentage of the additive is 10mol%;
the solvent is tetrahydrofuran, dioxane, dichloromethane, 1,2-dichloroethane or toluene;
the additive is iodine, N-iodosuccinimide, N-bromosuccinimide, N-chlorosuccinimide or tetrabutylammonium iodide.
2. The method of claim 1 for synthesizing a chiral α -amino acid ester derivative, wherein: the iridium-cyclooctadiene complex is: [ Ir (COD) Cl] 2 、Ir(COD) 2 BF 4 Or Ir (COD) 2 BARF。
3. The method of claim 1 for synthesizing a chiral α -amino acid ester derivative, wherein: the iridium concentration is 0.001-0.01mol/L, and the molar ratio of the chiral ferrocene skeleton phosphine-phosphoramidite ligand to iridium is 1-5:1.
4. the method of claim 1 for synthesizing a chiral α -amino acid ester derivative, wherein: the molar ratio of the alpha-imidate substrate to the chiral catalyst iridium-L is 50-500:1.
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| Title |
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| Highly Enantioselective Hydrogenation of Acyclic Imines Catalyzed by Ir ± f-Binaphane Complexes;Denming Xiao等;《Angewndte Chemie International Edition》;20010914;第40卷(第18期);第3427页Experimental Section部分，表2 Entry 2 * |
| Rh-Catalyzed Asymmetric Hydrogenation of a-Aryl Imino Esters: An Efficient Enantioselective Synthesis of Aryl Glycine Derivatives;Gao Shang等;《Angewndte Chemie International Edition》;20060828;第45卷;第6361页Experimental Section部分、表2 Entry 1 * |
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