CN113666851A - Optically pure chiral aminoacetal, preparation method and application thereof - Google Patents

Optically pure chiral aminoacetal, preparation method and application thereof Download PDF

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CN113666851A
CN113666851A CN202110799207.XA CN202110799207A CN113666851A CN 113666851 A CN113666851 A CN 113666851A CN 202110799207 A CN202110799207 A CN 202110799207A CN 113666851 A CN113666851 A CN 113666851A
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nitrobenzenesulfonamide
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田杰生
张深远
何雨
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Northwestern Polytechnical University
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    • C07C303/00—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides
    • C07C303/36—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids
    • C07C303/40—Preparation of esters or amides of sulfuric acids; Preparation of sulfonic acids or of their esters, halides, anhydrides or amides of amides of sulfonic acids by reactions not involving the formation of sulfonamide groups
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/16—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom
    • C07C311/17—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to hydrogen atoms or to an acyclic carbon atom to an acyclic carbon atom of a hydrocarbon radical substituted by singly-bound oxygen atoms
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    • C07C311/15—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings
    • C07C311/20—Sulfonamides having sulfur atoms of sulfonamide groups bound to carbon atoms of six-membered aromatic rings having the nitrogen atom of at least one of the sulfonamide groups bound to a carbon atom of a ring other than a six-membered aromatic ring
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Abstract

The invention discloses an optically pure chiral aminoacetal, a preparation method and application thereof. Adding 0.2-3 mmol of racemic p-nitrobenzenesulfonyl amino acetal, 0.2-3 mmol of aryl pinacol ester, 0.02-0.3 mmol of palladium acetate, 0.03-0.45 mmol of chiral amino acid ligand, 0.6-9 mmol of sodium carbonate, 0.4-6 mmol of silver carbonate, 0.1-1.5 mmol of 1, 4-benzoquinone, 0.08-1.2 mmol of dimethyl sulfoxide, 1-15 mmol of water and 1-15 mL of tert-amyl alcohol into a reaction vessel, uniformly mixing to obtain a mixture, reacting the mixture in an inert gas environment at 50 ℃ for 6-12 hours to obtain a reaction product, and purifying the reaction product to obtain optically pure chiral amino acetal; the chiral aminoacetal is used as an intermediate in the preparation of natural products of medicaments. The aminoacetal used in the method is prepared by the fatty aldehyde amination reaction with simple synthesis and high conversion rate, the substrate has wide application range, the required reaction condition is very mild, the reaction steps are few, and the operation is simple.

Description

Optically pure chiral aminoacetal, preparation method and application thereof
Technical Field
The invention belongs to the technical field of organic chemical synthesis, and particularly relates to an optically pure chiral aminoacetal, and a preparation method and application thereof.
Background
Chiral alpha-amino acetal as a new chiral alpha-amino acid derivative widely exists in various natural products and chiral drugs, and two adjacent carbon atoms of the chiral alpha-amino acetal respectively have the unique structures of acetal and amino functional groups, so that the chiral alpha-amino acetal becomes an important drug and a synthetic intermediate of the natural product. Chiral alpha-amino acid derivatives are widely available, and most representative of the derivatives are alpha-aminoaldehydes, alpha-aminoalcohols, alpha-aminoamides, alpha-aminocarboxylates, and the like, and these chiral amino acid derivatives can be obtained by simple conversion and modification of chiral alpha-aminoacetals. Based on the potential value of such α -aminoacetals in life science research, organic synthesis and biomedical research and development, great interest has been raised in numerous synthetic chemists over the last decades. In the field of medicine and among the numerous natural products, more than half of the drugs and natural products are chiral molecules. Therefore, the synthesis of a series of chiral amino acid derivatives and their application in the construction of chiral drugs and natural product scaffolds are one of the hot topics in synthetic chemistry today.
At present, enzymatic kinetic resolution, classical resolution by means of diastereomer salification and asymmetric phase transfer catalysis are the most commonly used synthetic methods and industrial production is achieved. However, the synthesis method has the defects of easy enzyme activation, easy racemization of products, poor separation effect, low atom utilization rate, harsh reaction conditions, waiting for improvement of the selectivity of the obtained enantiomer and the like. In addition, modification of natural α -amino acid derivatives by C-H functionalization is also a popular area of research by synthetic chemists today, however, the number of natural amino acids is limited and the substrate requires multiple protecting and deprotecting operations.
Therefore, the method has important significance and application value for preparing diversified alpha-aminoacetal by using commercial aliphatic aldehyde and secondary amine as raw materials and further preparing optically pure alpha-aminoacetal by dynamic resolution.
Disclosure of Invention
The invention aims to provide a preparation method of optically pure chiral aminoacetaldehyde, aiming at overcoming the defects of the prior art in the background technology.
It is a further object of the present invention to provide optically pure chiral aminoacetals obtained by the above-described preparation process.
It is a further object of the present invention to provide the use of the above optically pure chiral aminoacetals.
The invention is realized in such a way that a method for preparing an optically pure chiral aminoacetaldehyde comprises the following steps:
(1) adding 0.2-3 mmol of racemic p-nitrobenzenesulfonyl amino acetal, 0.2-3 mmol of aryl pinacol ester, 0.02-0.3 mmol of palladium acetate, 0.03-0.45 mmol of chiral amino acid ligand, 0.6-9 mmol of sodium carbonate, 0.4-6 mmol of silver carbonate, 0.1-1.5 mmol of 1, 4-benzoquinone, 0.08-1.2 mmol of dimethyl sulfoxide, 1-15 mmol of water and 1-15 mL of tert-amyl alcohol into a reaction container, uniformly mixing to obtain a mixture, and reacting the mixture at 50 ℃ for 6-12 hours in an inert gas environment to obtain a reaction product;
(2) purifying the reaction product to obtain the optically pure chiral aminoacetal.
Preferably, in step (1), the racemic p-nitrobenzenesulfonylamino acetal is selected from the group consisting of N- (2, 2-dimethoxy-1-phenylethyl) -4-nitrobenzenesulfonamide, N- (2, 2-dimethoxy-1- (o-tolyl) ethyl) -4-nitrobenzenesulfonamide, N- (2, 2-dimethoxy-1- (2-methoxyphenyl) ethyl) -4-nitrobenzenesulfonamide, N- (1- (2-fluorophenyl) -2, 2-dimethoxyethyl) -4-nitrobenzenesulfonamide, N- (2, 2-dimethoxy-1- (2- (trifluoromethyl) phenyl) ethyl) -4-nitrobenzenesulfonamide, N- (2, 2-dimethoxy-1-methyl) -4-nitrobenzenesulfonamide, N- (2-methoxy-1-ethyl) -4-nitrobenzenesulfonamide, N- (2-methyl) -4-nitrobenzenesulfonamide, N-benzyl-sulfonamide, N-methyl-or a salt, N-or a salt thereof, N- (1- (3-fluorophenyl) -2, 2-dimethoxyethyl) -4-nitrobenzenesulfonamide, N- (2, 2-dimethoxy-1- (3-methoxyphenyl) ethyl) -4-nitrobenzenesulfonamide, N- (2, 2-dimethoxy-1- (3- (trifluoromethyl) phenyl) ethyl) -4-nitrobenzenesulfonamide, N- (1- (2-, 3-difluorophenyl) -2, 2-dimethoxyethyl) -4-nitrobenzenesulfonamide, N- (1- (2,3, 4-trifluorophenyl) -2, 2-dimethoxyethyl) -4-nitrobenzenesulfonamide, N-isopropyl-N-isopropyl-4-nitrobenzenesulfonamide, N-isopropyl-methyl-2, 2-dimethoxyethyl-4-nitrobenzenesulfonamide, N-isopropyl-methyl-4-methyl-4-nitrobenzenesulfonamide, N-isopropyl-2, N-isopropyl-methyl-4-methyl-ethyl-4-methyl-ethyl-methyl-ethyl-methyl-4-methyl-ethyl-methyl-ethyl-4-phenyl-methyl-4-ethyl-methyl-ethyl-4-methyl-ethyl-methyl-ethyl-phenyl-ethyl-4-ethyl-methyl-4-methyl-ethyl-methyl-ethyl-4-methyl-ethyl-methyl-ethyl-4-methyl-ethyl-methyl-ethyl-methyl-ethyl-methyl-ethyl-methyl-ethyl-4-methyl, Any one of N- (3- (2-fluorophenyl) -1, 1-dimethoxypropan-2-yl) -4-nitrobenzenesulfonamide and N- (1- (benzo [ d ] [1,3] dioxa-5-yl) -2, 2-dimethoxyethyl) -4-nitrobenzenesulfonamide.
Preferably, in the step (1), the preparation process of the racemic p-nitrobenzenesulfonylamino acetal comprises the following steps:
A. adding 0.5-5 mmol of dibenzylamine, 0.6-6 mmol of aliphatic aldehyde, 0.75-7.5 mmol of sodium percarbonate, 0.1-1 mmol of iodine, 0.5-5 mL of methanol and 2-20 mL of 1, 2-dichloroethane into a reaction vessel, uniformly mixing to obtain a mixture 1, and reacting the mixture 1 at the temperature of 40-60 ℃ for 6-12 hours to obtain dibenzyl amino acetal;
B. 0.5-5 mmol of dibenzyl amino acetal obtained in the step A, Pd (OH)2Adding 10 wt% of/C and 0.5-5 mL of methanol into a reaction vessel, stirring for 12-24 hours at 20-50 ℃, and filtering to obtain debenzylated aminoacetal;
C. and C, adding 0.5-5 mmol of debenzylated aminoacetal obtained in the step B, 0.5-5 mmol of p-nitrobenzenesulfonyl chloride, 1.5-15 mmol of triethylamine and 2-20 mL of dichloromethane into a reaction container, uniformly mixing to obtain a mixture 2, and reacting the mixture 2 at the temperature of 0-25 ℃ for 5-12 hours to obtain racemic p-nitrobenzenesulfonylaminoacetal.
Preferably, in the step (1), the arylpinacol ester is selected from any one of pinacol ester phenylboronate, pinacol ester 4-esterylphenylborate, pinacol ester 4-fluorophenylborate, pinacol ester 4-chlorophenylborate, pinacol ester 4-trifluoromethylphenylboronate, pinacol ester 4-cyanophenylborate, pinacol ester 3-esterylphenylborate, and pinacol ester 2-fluoro-3-cyanophenylborate.
Preferably, in step (1), the inert gas is nitrogen.
Preferably, in the step (2), the reaction product is purified by thin layer chromatography, a developing solvent system is petroleum ether/ethyl acetate, and the using amount ratio of the petroleum ether to the ethyl acetate is 10-5: 1.
The invention further discloses chiral aminoacetal obtained by the preparation method, and the chemical formula of the chiral aminoacetal is shown as the following formula (I), formula (II) or formula (III):
Figure BDA0003163999900000031
Figure BDA0003163999900000041
in the formulae (I), (II) and (III), R1Selected from 2-Me, 2-OMe, 2-F, 2-CF3、3-F、3-OMe、3-CF3、2,3-2F、4-F、4-CF3、4-OMe、-OCH2Any one of O < - >; r3Any one selected from Me, Et and Ac;
in the formulae (II) and (III), R2Selected from H, 4-CO2Me、4-F、4-Cl、4-CF3、4-CN、3-CO2Any one of Me, 3-CN and 2-F-3-CN;
alternatively, the chiral aminoacetal has the formula (IV), (V) or (VI):
Figure BDA0003163999900000042
in the formulae (IV), (V) and (VI), R4Selected from 2-F, 2-CF3Any one of 3-OMe, 2, 3-2F; r5Any one selected from Me, Et and Ac;
in the formulae (V) and (VI), R6Selected from H, 4-CO2Me、4-F、4-Cl、4-CF3、4-CN、3-CO2Any one of Me, 3-CN and 2-F-3-CN.
The invention further discloses application of the chiral aminoacetal as an intermediate in preparation of medicines and synthesis of natural products.
Compared with the defects and shortcomings of the prior art, the invention has the following beneficial effects:
(1) the aminoacetal used in the method is prepared by the fatty aldehyde amination reaction with simple synthesis and high conversion rate, the substrate has wide application range, and is suitable for aromatic aminoacetal with various substituent groups, and the palladium catalyst and the chiral amino acid ligand used in the catalytic system are cheap, high in economy and wide in market source; the method of the invention has the characteristics of very mild reaction conditions, few reaction steps and simple operation;
(2) the optically pure alpha-aminoacetal prepared by the invention is taken as an important chiral alpha-aminoacid derivative, is widely distributed in biologically and pharmaceutically active molecules, can realize the synthesis of various chiral nitrogen heterocycles through simple conversion, and has wide application prospect in the synthesis of medicines and natural products.
Drawings
FIG. 1 is a nuclear magnetic resonance hydrogen spectrum of racemic N- (2, 2-dimethoxy-1- (o-tolyl) ethyl) -4-nitrobenzenesulfonamide in the present example;
FIG. 2 is a nuclear magnetic resonance carbon spectrum of racemic N- (2, 2-dimethoxy-1- (o-tolyl) ethyl) -4-nitrobenzenesulfonamide in the example of the present invention;
FIG. 3 is a nuclear magnetic resonance hydrogen spectrum of racemic N- (2, 2-dimethoxy-1- (o-methoxyphenyl) ethyl) -4-nitrobenzenesulfonamide in the example of the present invention;
FIG. 4 is a nuclear magnetic resonance carbon spectrum of racemic N- (2, 2-dimethoxy-1- (o-methoxyphenyl) ethyl) -4-nitrobenzenesulfonamide in an example of the present invention;
FIG. 5 is a NMR spectrum of racemic N- (3- (2-fluorophenyl) -1, 1-dimethoxypropan-2-yl) -4-nitrobenzenesulfonamide in an example of the present invention;
FIG. 6 is a NMR carbon spectrum of racemic N- (3- (2-fluorophenyl) -1, 1-dimethoxypropan-2-yl) -4-nitrobenzenesulfonamide in an example of the present invention;
FIG. 7 is a NMR fluorine spectrum of racemic N- (3- (2-fluorophenyl) -1, 1-dimethoxypropan-2-yl) -4-nitrobenzenesulfonamide in an example of the present invention;
FIG. 8 is a NMR spectrum of methyl (S) -2' - (2, 2-dimethoxy-1- (((4-nitrophenyl) sulfonamido) ethyl) -3' -methyl- [1,1' -biphenyl ] -4-carboxylate in accordance with an example of the present invention;
FIG. 9 is a NMR carbon spectrum of methyl 2' - (2, 2-dimethoxy-1- (((4-nitrophenyl) sulfonamide) ethyl) -3' -methyl- [1,1' -biphenyl ] -4-carboxylate in accordance with an example of the present invention;
FIG. 10 is a NMR spectrum of methyl (S) -2' - (2, 2-dimethoxy-1- (((4-nitrophenyl) sulfonamido) ethyl) -3' -methoxy- [1,1' -biphenyl ] -4-carboxylate in accordance with an example of the present invention;
FIG. 11 is a NMR carbon spectrum of methyl 2' - (2, 2-dimethoxy-1- (((4-nitrophenyl) sulfonamide) ethyl) -3' -methoxy- [1,1' -biphenyl ] -4-carboxylate in accordance with an example of the present invention;
FIG. 12 is a nuclear magnetic resonance hydrogen spectrum of (S) -N- (3- (3-fluoro- [1,1' -biphenyl ] -2-yl) -1, 1-dimethoxypropan-2-yl) -4-nitrobenzenesulfonamide in an example of the present invention;
FIG. 13 is a NMR carbon spectrum of (S) -N- (3- (3-fluoro- [1,1' -biphenyl ] -2-yl) -1, 1-dimethoxypropan-2-yl) -4-nitrobenzenesulfonamide in an example of the present invention;
FIG. 14 shows the NMR fluorine spectrum of (S) -N- (3- (3-fluoro- [1,1' -biphenyl ] -2-yl) -1, 1-dimethoxypropan-2-yl) -4-nitrobenzenesulfonamide in example of the present invention.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, the present invention is described in further detail below with reference to the accompanying drawings and embodiments. It should be understood that the specific embodiments described herein are merely illustrative of the invention and are not intended to limit the invention.
Example 1
A. Adding 1.0mmol of dibenzylamine, 1.2mmol of o-tolylacetaldehyde, 1.5mmol of sodium percarbonate, 0.2mmol of iodine, 1.0mL of methanol and 4mL of 1, 2-dichloroethane into a reaction vessel, uniformly mixing to obtain a mixture 1, and reacting the mixture 1 at 60 ℃ for 12 hours to obtain dibenzyl amino acetal;
B. 0.5mmol of dibenzylaminoacetal obtained in step A, Pd (OH)2C (10 wt%), and 0.5mL methanol into a reaction vessel, at 50 ℃ stirring for 12 hours, filtering to obtain debenzylated aminoacetal;
C. and C, adding 0.5mmol of debenzylated aminoacetal obtained in the step B, 0.5mmol of p-nitrobenzenesulfonyl chloride, 1.5mmol of triethylamine and 2mL of dichloromethane into a reaction vessel, uniformly mixing to obtain a mixture 2, and reacting the mixture 2 at the temperature of 0-25 ℃ for 12 hours to obtain racemic N- (2, 2-dimethoxy-1- (o-tolyl) ethyl) -4-nitrobenzenesulfonamide. The chemical structure and nuclear magnetic resonance image of the light yellow solid are shown in figures 1-2. The nuclear magnetic data characterization attributes are as follows: rf＝0.35(hexane:ethyl acetate＝3:1)；1H NMR(400MHz,CDCl3)δ8.05(d,J＝8.9Hz,2H),7.66(d,J＝8.9Hz,2H),7.02(m,2H),6.93(d,J＝7.6Hz,1H),6.81(m,1H),5.65(d,J＝5.8Hz,1H),4.90(m,1H),4.35(J＝4.7Hz,1H),3.35(s,3H),3.26(s,3H),2.36(s,3H)ppm；13C NMR(100MHz,CDCl3)ppm；δ149.41,146.40,136.35,134.06,130.21,128.09,127.78,127.49,125.81,123.48,105.78,56.09,55.21,55.07,19.40；HRMS(ESI-TOF)m/z Calcd for C16H17N2O6SH+[M+H]+381.1120,found 381.1126.
Example 2
A. Adding 1.0mmol of dibenzylamine, 1.2mmol of o-methoxyphenylacetaldehyde, 1.5mmol of sodium percarbonate, 0.2mmol of iodine, 1.0mL of methanol and 4mL of 1, 2-dichloroethane into a reaction vessel, uniformly mixing to obtain a mixture 1, and reacting the mixture 1 at 60 ℃ for 12 hours to obtain dibenzyl amino acetal;
B. 0.5mmol of dibenzylaminoacetal obtained in step A, Pd (OH)2C (10 wt%), and 0.5mL methanol into a reaction vessel, at 50 ℃ stirring for 12 hours, filtering to obtain debenzylated aminoacetal;
C. adding 0.5mmol of debenzylated aminoacetal obtained in the step B, 0.5mmol of p-nitrobenzenesulfonyl chloride, 1.5mmol of triethylamine and 2mL of dichloromethane into a reaction vessel, and uniformly mixing to obtain a mixtureAnd reacting the mixture 2 at the temperature of 0-25 ℃ for 12 hours to obtain racemic N- (2, 2-dimethoxy-1- (o-methoxyphenyl) ethyl) -4-nitrobenzenesulfonamide. The chemical structure and nuclear magnetic resonance image of the pale yellow solid are shown in figures 3-4. The nuclear magnetic data characterization attributes are as follows: rf＝0.35(he xane:ethyl acetate＝3:1)；1H NMR(400MHz,CDCl3)δ8.10(d,J＝7.8Hz,2H),7.82(d,J＝8.6Hz,2H),7.14(t,J＝7.8Hz,1H),7.07(d,J＝7.5Hz,1H),6.76(t,J＝7.5Hz,1H),6.68(d,J＝8.3Hz,1H),5.83(m,1H),4.82(m,1H),4.46(d,J＝4.7Hz,1H),3.76(s,3H),3.28(s,3H),3.20(s,3H)ppm；13C NMR(100MHz,CDCl3)δ156.29,149.56,146.63,129.63,129.33,128.36,124.42,123.56,120.73,110.43,104.35,55.92,55.45,55.16,55.07ppm；HRMS(ESI-TOF)m/z Calcd for C17H20N2O7SH+[M+H]+397.1069,found 397.1063.
Example 3
A. Adding 1.0mmol of dibenzylamine, 1.2mmol of o-fluorophenylpropionaldehyde, 1.5mmol of sodium percarbonate, 0.2mmol of iodine, 1.0mL of methanol and 4mL of 1, 2-dichloroethane into a reaction vessel, uniformly mixing to obtain a mixture 1, and reacting the mixture 1 at 60 ℃ for 12 hours to obtain dibenzyl amino acetal;
B. 0.5mmol of dibenzylaminoacetal obtained in step A, Pd (OH)2C (10 wt%), and 0.5mL methanol into a reaction vessel, at 50 ℃ stirring for 12 hours, filtering to obtain debenzylated aminoacetal;
C. and C, adding 0.5mmol of debenzylated aminoacetal obtained in the step B, 0.5mmol of p-nitrobenzenesulfonyl chloride, 1.5mmol of triethylamine and 2mL of dichloromethane into a reaction vessel, uniformly mixing to obtain a mixture 2, and reacting the mixture 2 at the temperature of 0-25 ℃ for 12 hours to obtain racemic N- (3- (2-fluorophenyl) -1, 1-dimethoxypropane-2-yl) -4-nitrobenzenesulfonamide. The chemical structure and nuclear magnetic resonance image of the pale yellow solid are shown in figures 5-7. The nuclear magnetic data characterization attributes are as follows: rf＝0.35(hexane:ethyl acetate＝3:1)；1H NMR(400MHz,CDCl3)δ8.07(d,J＝8.6Hz,2H),7.69(d,J＝8.8Hz,2H),7.07(m,1H),6.98(m,1H),6.87(td,J＝7.5Hz,1Hz,1H),6.75(m,1H),5.03(d,J＝9.2Hz,1H),4.34(d,J＝2.6Hz,1H),3.65(m,1H),3.49(s,3H),3.42(s,3H),2.93(dd,J＝14.2Hz,4.6Hz,1H),2.70(dd,J＝14.3Hz,10.2Hz,1H)；13C NMR(100MH z,CDCl3):δ162.27,159.84,149.44,146.10,131.69(d,J＝4.8Hz),129.21128.50(d,J＝1.7Hz),128.41,127.84,127.43,124.50,124.35,124.12(d,J＝3.6Hz),123.83,115.16(d,J＝22.1Hz),106.17,99.87,57.27,56.75,28.49(d,J＝1.8Hz)ppm；HRMS(ESI-TOF)m/z Calcd for C17H19FN2O6S H+[M+H]+399.1026,found 399.1030.
Examples 4 to 10
Examples 4-10 are similar to example 1, except that the fatty aldehyde is selected differently in step A, as shown in Table 1 below:
TABLE 1
Figure BDA0003163999900000081
Figure BDA0003163999900000091
Example 11
(1) In a 10mL Schlenk tube, racemic N- (2, 2-dimethoxy-1- (o-tolyl) ethyl) -4-nitrobenzenesulfonamide (0.10mmol, 0.046g), pinacol 4-esterphenylboronate (0.1mmol, 0.035g), palladium acetate (0.01mmol, 0.0023g), chiral amino acid ligand (0.015mmol, 0.0056g), and sodium carbonate (0.3mmol, 0.033g), silver carbonate (0.2mmol, 0.0553g), 1, 4-benzoquinone (0.05mmol, 0.056g), dimethyl sulfoxide (0.04mmol, 0.003mL), water (0.5mmol, 0.01mL) were added sequentially under nitrogen for a stirred reaction in 0.5mL of t-amyl alcohol for 6 hours, the equation:
Figure BDA0003163999900000092
(2) after TLC monitoring the reaction was complete, the mixture was dissolved with dichloromethane and the product was isolated by thin layer chromatography (petroleum ether/ethyl acetate 5:1) as compound 1 as a light yellow solid in 51% yield. The chemical structure and nuclear magnetic resonance image of the pale yellow solid are shown in figures 8-9.
A light yellow solid; rf＝0.33(hexane:ethyl acetate＝8:1)；1H NMR(400M Hz,CDCl3)δ8.12(m,4H),7.64(d,J＝8.6Hz,2H),7.41(s,1H),7.19(t,J＝7.6Hz,1H),7.01(dd,J＝21.9Hz,7.2Hz,2H),5.40(s,1H),4.75(s,1H),4.45(s,1H),3.97(s,3H),3.14(s,3H),2.92(s,3H),2.41(s,3H)；13C NMR(100MHz,CDCl3):δ166.78,149.52,146.35,137.32,137.22,128.99,128.22,127.72,123.59,104.46,55.78,55.67,53.56,52.27,21.23.HRMS(ESI-TOF)m/z Calcd for C25H26N2O8SH+[M+H]+515.1488,found 515.1490.HPLC,Chiralcel AD-H column(20％isopropanol in hexanes,0.8mL/min)tr 13.12min(major),22.46min(minor):92％ee.
Example 12
(1) In a 10mL Schlenk tube, racemic N- (2, 2-dimethoxy-1- (o-methoxyphenyl) ethyl) -4-nitrobenzenesulfonamide (0.10mmol, 0.040g), pinacol 4-esterphenylboronate (0.1mmol, 0.035g), palladium acetate (0.01mmol, 0.0023g), chiral amino acid ligand (0.015mmol, 0.0056g), and sodium carbonate (0.3mmol, 0.033g), silver carbonate (0.2mmol, 0.0553g), 1, 4-benzoquinone (0.05mmol, 0.056g), dimethyl sulfoxide (0.04mmol, 0.003mL), water (0.5mmol, 0.01mL) were added sequentially under nitrogen for a stirred reaction in 0.5mL of tertiary amyl alcohol for 6 hours, the equation:
Figure BDA0003163999900000101
(2) after TLC monitoring the reaction was complete, the mixture was taken out with dichloromethane and the product was isolated by thin layer chromatography (petroleum ether: ethyl acetate 5:1) as light yellow liquid compound 2 in 47% yield. The chemical structure and nuclear magnetic resonance image of the light yellow solid are shown in fig. 10-11.
A light yellow solid; mp 137.9-138.8 ℃; rf＝0.33(hexane:ethyl acetate＝8:1)；1H NMR(400MHz,CDCl3)δ8.10(dd,J＝12.7Hz,8.5Hz,4H),7.67(d,J＝8.9Hz,2H),7.44(s,1H),7.23(d,J＝7.9Hz,1H),7.79(dd,J＝8.1Hz,1.6Hz,2H),6.13(d,J＝9.2Hz,1H),4.69(m,2H),3.96(s,3H),3.84(s,3H),3.10(s,3H),3.03(s,3H)；13C NMR(100MHz,CDCl3):δ166.96,156.99,149.37,146.77,144.72,143.06,129.18,129.07,128.91,128.04,123.45,110.30,104.22,56.21,55.64,55.00,52.52,52.21.HRMS(ESI-TOF)m/z Calcd for C25H26N2O9SH+[M+H]+531.1437,found 531.1435.
HPLC,Chiralcel AD-H column(20％isopropanol in hexanes,0.8mL/min)tr 18.5min(major),31.4min(minor):94％ee.
Example 13
(1) In a 10mL Schlenk tube, racemic N- (3- (2-fluorophenyl) -1, 1-dimethoxypropan-2-yl) -4-nitrobenzenesulfonamide (0.10mmol, 0.040g), pinacol phenylboronate (0.1mmol, 0.024g), palladium acetate (0.01mmol, 0.0023g), chiral amino acid ligand (0.015mmol, 0.0056g) and sodium carbonate (0.3mmol, 0.033g), silver carbonate (0.2mmol, 0.0553g), 1, 4-benzoquinone (0.05mmol, 0.056g), dimethyl sulfoxide (0.04mmol, 0.003mL), water (0.5mmol, 0.01mL) were added sequentially under nitrogen for a stirred reaction in 1.5mL of t-amyl alcohol for 6 hours, the equation:
Figure BDA0003163999900000111
(2) after TLC monitoring the reaction was complete, the mixture was taken out with dichloromethane and the product was isolated by thin layer chromatography (petroleum ether: ethyl acetate 5:1) as 3 as a light yellow solid in 48% yield. The chemical structure and nuclear magnetic resonance image of the light yellow solid are shown in FIGS. 12-14.
A light yellow solid; rf＝0.33(hexane:ethyl acetate＝8:1)；1H NMR(400MHz,CDCl3)δ8.12(d,J＝9.0Hz,2H),7.67(d,J＝8.9Hz,2H),7.42(m,3H),7.13(m,2H),7.08(m,1H),6.84(d,J＝7.6Hz,1H),6.76(m,1H),4.80(d,J＝9.5Hz,1H),4.05(d,J＝2.6Hz,1H),3.36(m,1H),3.23(s,3H),3.08(s,3H),2.93(m,1H),2.82(m,1H)；13C NMR(100MHz,CDCl3):δ162.57,160.14,149.42,146.44,144.55(d,J＝4.2Hz),139.66(d,J＝2.9Hz),128.92,128.52,127.75,127.66,127.62,127.59,125.83(d,J＝3.2Hz),123.84,122.77,122.62,114.23,114.00,106.03,56.33,56.02,55.74(d,J＝1.9Hz),23.98(d,J＝2.9Hz).
HPLC,Chiralcel AD-H column(20％isopropanol in hexanes,0.8mL/min)tr 12.5min(major),17.0min(minor):91％ee.
Example 14
(1) In a 10mL Schlenk tube, (R) -N-benzyl-N- (2, 2-dimethoxy-1- (2- (trifluoromethyl) phenyl) ethyl) -4-nitrobenzenesulfonamide (compound A) and FeCl were added in sequence under nitrogen atmosphere3(0.2mmol, 0.033g) and dichloromethane as a solvent, and stirring the mixture at-20 ℃ for 0.5 hour, the reaction equation is:
Figure BDA0003163999900000121
(2) after completion of the TLC detection reaction, the solvent was distilled off under reduced pressure, and the product was isolated by thin layer chromatography (petroleum ether: ethyl acetate 10:1) as light yellow solid compound B in 88% yield.
Example 15
(1) In a 10mL test tube, (R) -N- (2, 2-dimethoxy-1-phenylethyl) -4-nitro-N- (2-phenylallyl) benzenesulfonamide (compound C), TfOH (0.2mmol, 0.031g) and dichloromethane were added in this order as a solvent, and the reaction was stirred at 20 ℃ for 0.5 hour, the reaction equation was:
Figure BDA0003163999900000131
(2) after completion of the TLC detection reaction, the solvent was distilled off under reduced pressure and the product was isolated by thin layer chromatography (petroleum ether: ethyl acetate 10:1) as white solid compound D in 90% yield.
Example 16
(1) In a 10mL Schlenk tube, (R) -N- (2, 2-dimethoxy-1- (2- (trifluoromethyl) phenyl) ethyl) -N- (3-methyl-2-en-1-yl) -4-nitrobenzenesulfonamide (compound E), TfOH (0.2mmol, 0.031g) and dichloromethane as solvent are added in sequence under nitrogen atmosphere, and the reaction is stirred at 0 ℃ for 0.5 hour with the reaction equation:
Figure BDA0003163999900000132
(2) after TLC monitoring the reaction was complete, the mixture was dissolved in dichloromethane and the product was isolated by thin layer chromatography (petroleum ether/ethyl acetate 10:1) as white solid compound F in 89% yield.
Example 17
(1) In a 10mL Schlenk tube, (R) -N- (2, 2-dimethoxy-1- (3- (trifluoromethyl) - [1,1' -biphenyl) was added in sequence under nitrogen atmosphere]-2-yl) ethyl) -4-nitrobenzenesulfonamide (compound G), FeCl3(0.2mmol, 0.033g) in methylene chloride as a solvent, and stirred at-20 ℃ for 0.5 hours, the reaction equation is:
Figure BDA0003163999900000141
(2) after TLC monitoring the reaction was complete, the mixture was dissolved with dichloromethane and the product was isolated by thin layer chromatography (petroleum ether/ethyl acetate 10:1) as compound H as a light yellow solid in 80% yield.
Examples 18 to 25
The present examples 18 to 25 are substantially the same as the above example 11, and the differences are shown in the following table 2:
TABLE 2 Difference comparison
Figure BDA0003163999900000142
The above description is only for the purpose of illustrating the preferred embodiments of the present invention and is not to be construed as limiting the invention, and any modifications, equivalents and improvements made within the spirit and principle of the present invention are intended to be included within the scope of the present invention.

Claims (8)

1. A preparation method of optically pure chiral aminoacetaldehyde is characterized by comprising the following steps:
(1) adding 0.2-3 mmol of racemic p-nitrobenzenesulfonyl amino acetal, 0.2-3 mmol of aryl pinacol ester, 0.02-0.3 mmol of palladium acetate, 0.03-0.45 mmol of chiral amino acid ligand, 0.6-9 mmol of sodium carbonate, 0.4-6 mmol of silver carbonate, 0.1-1.5 mmol of 1, 4-benzoquinone, 0.08-1.2 mmol of dimethyl sulfoxide, 1-15 mmol of water and 1-15 mL of tert-amyl alcohol into a reaction container, uniformly mixing to obtain a mixture, and reacting the mixture at 50 ℃ for 6-12 hours in an inert gas environment to obtain a reaction product;
(2) purifying the reaction product to obtain the optically pure chiral aminoacetal.
2. The process for preparing an optically pure chiral aminoacetal according to claim 1 wherein, in step (1), the racemic p-nitrobenzenesulfonylaminoacetal is selected from the group consisting of N- (2, 2-dimethoxy-1-phenylethyl) -4-nitrobenzenesulfonamide, N- (2, 2-dimethoxy-1- (o-tolyl) ethyl) -4-nitrobenzenesulfonamide, N- (2, 2-dimethoxy-1- (o-methoxyphenyl) ethyl) -4-nitrobenzenesulfonamide, N- (1- (2-fluorophenyl) -2, 2-dimethoxyethyl) -4-nitrobenzenesulfonamide, N- (2, 2-dimethoxy-1- (2- (trifluoromethyl) phenyl) ethyl) -4-nitrobenzenesulfonamide Sulfonamides, N- (1- (3-fluorophenyl) -2, 2-dimethoxyethyl) -4-nitrobenzenesulfonamide, N- (2, 2-dimethoxy-1- (3-methoxyphenyl) ethyl) -4-nitrobenzenesulfonamide, N- (2, 2-dimethoxy-1- (3- (trifluoromethyl) phenyl) ethyl) -4-nitrobenzenesulfonamide, N- (1- (2-, 3-difluorophenyl) -2, 2-dimethoxyethyl) -4-nitrobenzenesulfonamide, N- (1- (2,3, 4-trifluorophenyl) -2, 2-dimethoxyethyl) -4-nitrobenzenesulfonamide, N-benzyl-N-2, 2-dimethoxyethyl-4-nitrobenzenesulfonamide, N-tert-methoxybenzenesulfonamide, N-nitrobenzenesulfonamide, N-benzyl-methyl-ethyl-4-nitrobenzenesulfonamide, N-methyl-ethyl-methyl-ethyl-methyl-ethyl-4-methyl-ethyl-methyl-ethyl-4-methyl-ethyl-methyl-ethyl-4-ethyl-methyl-ethyl-4-ethyl-methyl-ethyl-methyl-ethyl-methyl-ethyl-methyl-ethyl-methyl-ethyl-4-ethyl-methyl-ethyl-4-methyl-, Any one of N- (3- (2-fluorophenyl) -1, 1-dimethoxypropan-2-yl) -4-nitrobenzenesulfonamide and N- (1- (benzo [ d ] [1,3] dioxa-5-yl) -2, 2-dimethoxyethyl) -4-nitrobenzenesulfonamide.
3. The process for preparing an optically pure chiral aminoacetaldehyde according to claim 1, wherein in step (1), the process for preparing the racemic p-nitrobenzenesulfonylaminoacetaldehyde is:
A. adding 0.5-5 mmol of dibenzylamine, 0.6-6 mmol of aliphatic aldehyde, 0.75-7.5 mmol of sodium percarbonate, 0.1-1 mmol of iodine, 0.5-5 mL of methanol and 2-20 mL of 1, 2-dichloroethane into a reaction vessel, uniformly mixing to obtain a mixture 1, and reacting the mixture 1 at the temperature of 40-60 ℃ for 6-12 hours to obtain dibenzyl amino acetal;
B. 0.5-5 mmol of dibenzyl amino acetal obtained in the step A, Pd (OH)2Adding 10 wt% of/C and 0.5-5 mL of methanol into a reaction vessel, stirring for 12-24 hours at 20-50 ℃, and filtering to obtain debenzylated aminoacetal;
C. and C, adding 0.5-5 mmol of debenzylated aminoacetal obtained in the step B, 0.5-5 mmol of p-nitrobenzenesulfonyl chloride, 1.5-15 mmol of triethylamine and 2-20 mL of dichloromethane into a reaction container, uniformly mixing to obtain a mixture 2, and reacting the mixture 2 at the temperature of 0-25 ℃ for 5-12 hours to obtain racemic p-nitrobenzenesulfonylaminoacetal.
4. The process for preparing an optically pure chiral aminoacetaldehyde according to claim 1, wherein in the step (1), the arylpinacol ester is selected from any one of pinacol ester phenylboronate, pinacol ester 4-carbenylphenylboronate, pinacol ester 4-fluorobenzeneborate, pinacol ester 4-chlorobenzeneborate, pinacol ester 4-trifluoromethylphenylboronate, pinacol ester 4-cyanophenylborate, pinacol ester 3-carbenylphenylboronate, pinacol ester 2-fluoro-3-cyanophenylborate.
5. The process for preparing an optically pure chiral aminoacetaldehyde according to claim 1, wherein in step (1), the inert gas is nitrogen.
6. The method for preparing an optically pure chiral aminoacetaldehyde according to claim 1, wherein in the step (2), the reaction product is purified by thin layer chromatography, the developing solvent system is petroleum ether/ethyl acetate, and the ratio of the petroleum ether to the ethyl acetate is 10-5: 1.
7. The chiral aminoacetal obtained by the preparation method of any one of claims 1 to 6, characterized in that the chemical formula of the chiral aminoacetal is shown as the following formula (I), formula (II) or formula (III):
Figure FDA0003163999890000031
in the formulae (I), (II) and (III), R1Selected from 2-Me, 2-F, 2-CF3、3-F、3-OMe、3-CF3、2,3-2F、4-F、4-CF3、4-OMe、-OCH2Any one of O < - >; r3Any one selected from Me, Et and Ac;
in the formulae (II) and (III), R2Selected from H, 4-CO2Me、4-F、4-Cl、4-CF3、4-CN、3-CO2Any one of Me, 3-CN and 2-F-3-CN;
alternatively, the chiral aminoacetal has the formula (IV), (V) or (VI):
Figure FDA0003163999890000032
in the formulae (IV), (V) and (VI), R4Selected from 2-F, 2-CF3Any one of 3-OMe, 2, 3-2F; r5Any one selected from Me, Et and Ac;
in the formulae (V) and (VI), R6Selected from H, 4-CO2Me、4-F、4-Cl、4-CF3、4-CN、3-CO2Any one of Me, 3-CN and 2-F-3-CN.
8. Use of the chiral aminoacetals of claim 7 as intermediates in the preparation of pharmaceuticals and in the synthesis of natural products.
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CN104628730A (en) * 2014-09-12 2015-05-20 中山大学 Method for synthesizing optical pure chiral cyclic N,N-acetal
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CN104628730A (en) * 2014-09-12 2015-05-20 中山大学 Method for synthesizing optical pure chiral cyclic N,N-acetal
CN107382783A (en) * 2017-07-17 2017-11-24 中国科学院化学研究所 A kind of chiral beta amino acid derivativges and preparation method thereof

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